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An overview of the innate immune system

An overview of the innate immune system
Literature review current through: Aug 2023.
This topic last updated: Apr 06, 2023.

INTRODUCTION — Humans live in an environment teeming with microorganisms and could not exist as a species without highly effective mechanisms of host defense. The innate immune system constitutes the body’s first-line barriers and rapid-response mechanisms against microbial invasion.

This topic will review the cells, proteins, and receptors that comprise the innate immune system, the functional differences between innate and acquired immune responses, and the mechanisms by which the two systems interact. Disorders of innate immunity and more specific topics on individual types of cells and receptors are presented separately. (See "Toll-like receptors: Roles in disease and therapy" and "Complement pathways".)

CRITICAL FUNCTIONS — Medzhitov and Janeway defined innate immunity as a system of rapid immune responses that are present from birth and not adapted or permanently heightened as a result of exposure to microorganisms, in contrast to the responses of T and B lymphocytes in the adaptive immune system [1-3]. The innate immune system protects the host during the time between microbe exposure and initial adaptive responses. The importance of such a system can be appreciated by considering that the generation time of most bacteria is 20 to 30 minutes, whereas the development of a specific adaptive immune response with antibody and T cells takes days to weeks. Essential functions of the innate immune system include the following:

Detection of microorganisms and first-line defense against invasion and infection. (See 'Microbial detection through pattern recognition' below.)

Maintenance of "immunologic homeostasis," the balance between the proinflammatory mechanisms of host defense and the antiinflammatory responses that return the host to a healthy baseline. The cardinal signs of inflammation (tumor, rubor, calor, and dolor [swelling, redness, heat, and pain]) are products of the protective action of innate immunity. To limit damage to the host, these responses must also be terminated when no longer needed. (See 'Homeostasis in the innate immune system' below.)

Activation and instruction of adaptive immune responses. (See "The adaptive humoral immune response" and "The adaptive cellular immune response: T cells and cytokines".)

COMPONENTS OF INNATE IMMUNITY — These host defense components are evolutionarily ancient, found in all multicellular organisms, and expressed in humans as conserved elements (homologs) shared with other vertebrates and, in some form, with insects, plants, fungi, and bacteria [4-9]. Components of the innate immune system include those of the host itself and also its resident microbes, the microbiome. Embedded in the list of host components below is a vast array of cells, receptors, and molecules that are involved in eliminating enemies of host survival and a similar spectrum of components involved in returning the body's physiology to its baseline. These elements are grouped into units of biological function that capture the extraordinary breadth of mechanisms that evolution has brought forward as the system of innate immunity.

Host components

Physical barriers – Tight junctions between skin cells, epithelial and mucous membrane surfaces, mucus itself, and blood vessel endothelial cells that prevent pathogen penetration of the intestines [10-13]

Antimicrobial enzymes in epithelial and phagocytic cells (eg, lysozyme)

Inflammation-related serum proteins (eg, complement components, C-reactive protein [CRP], and lectins [carbohydrate-binding proteins])

Antimicrobial peptides (AMPs; defensins, cathelicidins, and many more) on the surfaces of cells and within phagocyte granules

An interferon (IFN) gamma-stimulated cytosolic apolipoprotein that can kill cytosolic bacteria (apolipoprotein L3 [APOL3]) [14]

Cell receptors that sense microorganisms and signal a defensive response (eg, Toll-like receptors [TLRs])

Cells that release cytokines and other mediators of the inflammatory response (eg, macrophages, mast cells, natural killer [NK] cells, innate lymphoid cells [ILCs])

Cytokines, cell-cell communicating and signaling proteins that mediate and regulate immunity, inflammation, and hematopoiesis, including chemokines, IFNs, interleukins (ILs), lymphokines, and tumor necrosis factor (TNF) [15]

Phagocytes (neutrophils, monocytes, macrophages)

Inflammasomes, central signaling systems that regulate the innate inflammatory response

The microbiome of the host

The microbiome — The microbiome, the collection of bacteria, fungi, and viruses that live in and on the body, may also be considered a component of the innate immune system as it profoundly impacts mechanisms of host defense [16-31]. The body's microbial composition directly influences the maturation of the immune response and its continued effectiveness, protects against pathogen overgrowth, and modulates the balance between inflammation and immune homeostasis [21,32-37]. For example, skin microbes interact with the immune system to promote wound healing [31,38]. Nonpathogenic coagulase-negative staphylococci on the skin produce an antimicrobial peptide that can inhibit growth of pathogenic Staphylococcus aureus. These protective strains are deficient in atopic dermatitis [39,40]. Oral microbiota can form symbiotic biofilms that balance pH levels and suppress pathogen growth in the mouth [41]. There are now convincing data that the gut microbiome influences the nervous system, and there are efforts to determine the mechanism and to develop drugs capable of acting on the brain [42-45].

The term "dysbiosis" refers to an underlying impairment of the functions that regulate gut homeostasis reflected as a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to a pattern associated with disease or a predisposition to disease, including Crohn disease and ulcerative colitis [21-23,46-53]. Antibiotic use is the classic cause, and Clostridioides difficile infection is a common, serious expression. Fecal microbiota transplantation (FMT) has been an effective method of treatment, though not without risk [54-57]. FMT has also improved remission rates of inflammatory bowel disease and chronic bacterial vaginosis [56-60]. (See "Treatment of irritable bowel syndrome in adults", section on 'Other therapies'.)

Dysbiosis is believed to play a role in development of obesity, type 2 diabetes, coronary artery disease, food allergy, asthma, and atopic dermatitis [22,34,61-64]. Because of its role as an orchestrator of biologic processes, the microbiome offers an attractive target for therapeutic intervention [65]. Manipulation of the gut microbiome through dietary change has been used with some success to treat type 2 diabetes [66,67], malnourished children [68-70], and immunotherapy-refractory melanoma [71-73]. The microbiome-derived metabolite trimethylamine N-oxide (TMAO) promotes immune activation and boosts immune checkpoint blockade in pancreatic cancer [74].

INNATE VERSUS ADAPTIVE IMMUNITY

The innate immune system recognizes microbes directly through pattern recognition receptors (PRRs), which are receptors specific for molecular components unique to microorganisms. The genes encoding PRRs are passed from parent to offspring. Phylogenetic studies have indicated that genes for PRRs and other components of the innate immune system have been gradually modified over generations by natural selection [1,3,4].

In contrast, each T and B lymphocyte acquires a structurally unique receptor during development, yielding a vast repertoire of cells with individualized receptors. From this repertoire, cells exposed to their unique microbial or other foreign antigen expand as a clone of cells directed at that specific antigen. As the clone expands, both the tightness (affinity) of the binding and the specificity for its particular antigen increase. Thus, the most useful receptors are selected and improved in the host over time. However, the "learned" immune responses and refinements made to the adaptive system cannot be passed on to an individual's progeny. (See "The adaptive cellular immune response: T cells and cytokines" and "The adaptive humoral immune response".)

Training of innate immunity — The principle of "cross protection" in host defense was first demonstrated in the 1960s. Innate macrophages that had been "activated" during infection to one pathogen were modified so that they were able to kill a second, unrelated organism more effectively. This heightened state waned rapidly once the pathogen (primary stimulus) was eliminated [75]. Later work showed that macrophages could be "primed" (imprinted) for enhanced expression of microbicidal mechanisms and pathogen killing by exposure to microbial components such as lipopolysaccharide (LPS) [76] and that small amounts of LPS can prime neutrophils for increased expression of microbicidal mechanisms on exposure to a variety of stimuli [77].

It is now clear that cells of the innate immune system can be trained by past infection, exposure to vaccines such as Bacillus Calmette-Guérin (BCG), or contact with microbial components such as LPS so that they have an enhanced response to the original or another trigger. The trained state is conferred by epigenetic reprogramming of transcriptional pathways, not gene recombination [78-81]. The lifespan of trained monocytes and neutrophils is short, but marrow hematopoietic stem cells (HSCs) can conserve epigenetic memory of previous infections and are long-lived, with self-renewal properties that maintain lifelong production of innate immune cells [82].

The principle of cross protection as expressed by trained innate immune cells has obvious implications for clinical medicine [83]. Randomized trials in Guinea-Bissau have shown that BCG vaccine administered at birth to low-weight infants significantly reduced death from infectious disease within the first month and first year of life [84]. BCG given to volunteers four weeks prior to administration of yellow fever vaccine significantly reduced the viral load after inoculation with the vaccine virus [85]. Trained innate immunity harnessed in this way has the potential to aid cancer therapies, sepsis-associated immune paralysis, and perhaps even resistance to novel viral outbreaks such as that by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [86]. Large-scale epidemiologic studies suggest that national programs in BCG vaccination reduce the mortality of coronavirus disease 2019 (COVID-19) [87,88]. National programs in vaccination with BCG, measles, or oral polio vaccine have also decreased all-cause mortality or respiratory infections in adolescents or older adults [89].

The inflammatory response that is essential for resistance to infection is abated by an antiinflammatory response as the host begins to win the battle. In this same sense, epigenetic changes like those that drive protective cross-specific immunity drive an antigen-nonspecific suppression of immunity. Although this response is useful in the short term, its persistence has the potential to dampen the response to future infection [89].

MICROBIAL DETECTION THROUGH PATTERN RECOGNITION — Innate immune responses to infection are largely mediated by a variety of proteins that recognize and interact with components that are specific to microbes. These proteins are grouped in their broad biologic context as "pattern recognition receptors" (PRRs) to emphasize their common function in host defense. The molecular components of microorganisms recognized by PRRs are called pathogen-associated molecular patterns (PAMPs). PRRs also recognize damage-associated molecular patterns (DAMPS) released as a consequence of tissue injury from inflammation or other causes.

Pathogen-associated molecular patterns — PRRs are capable of distinguishing between self-tissues and microbes by recognizing highly conserved PAMPs. Each type of PAMP is characteristic of a specific group of microbes.

All PAMPs have certain features in common:

They are produced only by microbes.

They are typically invariant structures shared by entire classes of pathogens.

Their structures are usually fundamental to the integrity, survival, and pathogenicity of the microorganisms, such that a microbe cannot mutate its PAMPs to avoid the host's defense mechanisms and still survive.

Bacterial endotoxin (lipopolysaccharide [LPS]), a component of the outer membrane of all gram-negative bacteria, is a prototypical PAMP. Endotoxin contains lipid A, a highly conserved structure of the lipid bilayer of the outer bacterial cell membrane that confers many of endotoxin's biologic activities [90]. Lipid A specifically interacts with Toll-like receptor (TLR) 4 (see 'Toll-like receptors' below). Other examples of PAMPs include the following:

Membrane components common to large categories of bacteria, such as peptidoglycan, lipoteichoic acids, and mannans

Unmethylated microbial deoxyribonucleic acid (DNA)

Double-stranded ribonucleic acid (RNA) of viral origin

Glucans, polysaccharides, or proteins that are common to microbes but not to animals or humans

Damage-associated molecular patterns — DAMPs or "alarmins" are nuclear, mitochondrial, or cytosolic molecules released from host cells as a result of infection, tissue injury, or cell necrosis. These molecules include high-mobility group box 1 (HMGB1), S100 proteins, heat-shock proteins, and adenosine triphosphate (ATP). Once released extracellularly, alarmins are recognized by PRRs on cells of the innate immune system, which promotes their removal but activates the cells to release proinflammatory cytokines that can promote serious illness, even sepsis syndrome [91,92].

Pattern recognition receptors — PRRs are divided into two broad groups: Secreted and circulating proteins and peptides and transmembrane and intracellular signal-transducing receptors (receptors in the more traditional sense). Some of the best studied molecules are discussed here.

Secreted and circulating PRRs — Secreted and circulating pattern recognition molecules include antimicrobial peptides (AMPs), collectins, lectins, pentraxins, and C1q of the complement system. These proteins and peptides mediate direct microbial killing, act as helper proteins for transmembrane receptors, and function as enhancers of phagocytosis (opsonins) by immune effector cells. Prototypic secreted and circulating PRRs include the following (table 1).

The complement system — The first component of complement, C1q is both a circulating and a cell-associated PRR that plays a broad role in host protection. When C1q binds to antibody that is fixed to a microbe, to damaged cells or tissues, or to immune complexes, it triggers the complement cascade, a key effector system of the innate immune response. The resulting attachment of C3b opsonizes (promotes phagocytosis of) the microbe or particle, generates chemotactic factors, and triggers fixation of the later-acting components that comprise the membrane-attack complex, which can directly lyse some microbes [93,94]. Complement activation is not confined to the extracellular space but also occurs within immune cells to stabilize intracellular metabolism in the basal state or during response to infection [95,96]. Because complement's potent inflammatory response to infection is also deployed when it is triggered by the immune complexes or autoantibodies of collagen-vascular disease or in other inflammatory conditions, the system is the target of intense investigation into possible therapeutic interventions [94,97-99]. (See 'Collectins' below and "Complement pathways".)

Antimicrobial peptides — AMPs are a group of secreted PRRs that are important in the protection of the skin and mucosal membranes and in the killing of phagocytosed organisms. AMPs secreted onto epithelial surfaces at a site of injury create a microbicidal shield that damages microorganisms prior to attachment and invasion. AMPs function synergistically and are microbicidal against a broad range of bacteria, fungi, chlamydiae, parasites, and enveloped viruses [30,100-114]. They are strategically placed anatomically (eg, single-cell RNA sequencing of the kidney shows transcripts for AMPs in the pelvic epithelium, where exposure to potential pathogens is high [115]).

Petrolatum, commonly used in the management of atopic dermatitis, increases the concentration of AMPs in the skin to which it is applied [116]. A database of over 1200 AMPs published in 2009 links amino acid composition to activity against specific types of microorganisms [111].

AMPs form pores through the outer membranes of a microbe that disrupt the membrane integrity and lead to death of the microbe. AMPs exist in many different forms and structures, but all contain clusters of hydrophobic, cationic (positively charged) amino acids that bind to negatively charged phospholipids in the outer bilayer of bacterial membranes. The outer cell membranes of animals contain lipids (including cholesterol) that differ from those of microbes, and AMPs are not attracted to them. Families of AMPs include the following:

Defensins, which are divided into alpha- and beta-defensins:

Human alpha-defensins 1 to 4 (HDs 1 to 4) are contained in the azurophilic granules of neutrophils and are also synthesized by Paneth cells at the base of small intestinal crypts (alpha-defensins 5 and 6) [102,104,106,117]. Defensins are short peptides (30 to 45 amino acids) that have three disulfide bonds that protect the peptide from protease degradation. They comprise 2 to 4 percent of the neutrophil cellular protein and are released into the phagocytic vacuole with captured organisms. HD5 kills microbes directly. HD6 does not kill directly but forms microscopic net-like mesh works (nanonets) that entrap the microbes, as do the extracellular traps that are released from dying neutrophils [106,107]. Evidence suggests that defective production of HDs 5 and 6 by Paneth cells plays a role in initiating inflammation in Crohn disease [117].

Human beta-defensins 1 to 6 (HBDs 1 to 6) are expressed on all epithelial surfaces, including those of the airways, urinary and gastrointestinal tracts, mouth, cornea and conjunctivae, and skin. Their production by epithelial cells can be constitutive (baseline, unstimulated) or inducible. Infectious or traumatic injury of epithelium elicits inflammatory cytokines that induce beta-defensin production [102,110,118]. Deficiency of HBD1 in sperm is associated with male infertility due to decreased motility and bactericidal activity [119].

Cathelicidins are a family of AMPs widely distributed in nature. The human cathelicidin LL-37 is released from both neutrophils and epithelial cells. It exhibits a broad range of antimicrobial activities [103,105,120], neutralizes LPS, and plays a role in wound healing, angiogenesis, and clearance of dead cells. LL-37 is induced by vitamin D [121-123]. In both keratinocytes and macrophages, stimulation of TLR2 results in the induction of the cytochrome P450 enzyme that converts vitamin D to its active form, which in turn induces the expression of LL-37. In this way, vitamin D can influence microbicidal defenses of both skin and circulating phagocytic cells [124]. This may explain, at least in part, why certain human infections (eg, tuberculosis) are more prevalent among populations with inadequate plasma levels of vitamin D, including those with more deeply pigmented skin [124]. (See "Vitamin D and extraskeletal health", section on 'Immune system'.)

Bacterial permeability-increasing protein (BPI) is expressed in neutrophil azurophilic granules and in oral, pulmonary, and gastrointestinal mucosal surfaces [125]. It selectively damages membranes of gram-negative bacteria and can opsonize the bacteria for phagocytosis by neutrophils. It has a high affinity for the lipid A region of LPS, which gives it the capacity to downregulate the effects of LPS on inflammation.

Epithelial and innate immune cells express other AMPs from several different structural classes across the body. Examples include:

C-terminal fragments of keratin released from corneal epithelial cells, which protect the cornea from infection, as do lysozyme, lactoferrin, and lipocalin in tears [126,127].

The bacteriostatic protein lipocalin 2 is secreted by alpha-intercalated cells in the collecting duct of the kidney, which also acidify the urine and defend against upper and lower urinary tract infection by binding uropathogenic Escherichia coli [128].

The glycoprotein uromodulin, the most abundant protein in human urine, forms filaments that bind to the pili of pathogenic bacteria, preventing their binding to urinary tract epithelium and allowing them to be flushed away with urine [129,130].

Hepcidin, a master regulator of iron metabolism that influences absorption and distribution of dietary iron. It has antimicrobial capacity against iron-dependent organisms such as malaria, tuberculosis, and human immunodeficiency virus 1 (HIV-1) [131-136].

Several chemokines, small chemotactic proteins that control migration of leukocytes into body tissues [137].

The existence of this broad repertoire of AMPs may in part explain the rarity of AMP resistance among pathogenic microbes. However, a second major function of these peptides is to govern the composition of the commensal microorganisms that colonize our body surfaces. These species, which lack the attributes of major pathogens, can be relatively resistant to AMPs and thus may have had an evolutionary advantage over other microbes in adapting to this niche [100,103,138,139]. In fact, human gut microbes from all dominant species can resist even the high levels of AMPs secreted in response to inflammation [140].

Inherited variability in defensin gene expression has been reported to contribute to the risk of several diseases, including Crohn disease and psoriasis, and research suggests that AMPs play a part in the pathophysiology of other diseases, such as atopic dermatitis and necrotizing enterocolitis [102]. Neutrophils and saliva in children with Kostmann severe congenital neutropenia are deficient in defensins and LL-37. These children suffer life-threatening infections and severe periodontal disease. Granulocyte colony-stimulating factor administration corrects the neutropenia but not the periodontitis. Bone marrow transplantation restores salivary LL-37 and allows control of the periodontal disease [141]. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Antibacterial oligosaccharides — A mother's milk protects her newborn against infection, at least in part through the antibodies and AMPs present in the milk. Human milk also contains oligosaccharides that have a direct antibacterial effect and a capacity to break down biofilms that bacteria use to protect themselves, thereby improving effectiveness of other antimicrobial agents [142].

Collectins — The collectins represent another type of secreted PRR (table 1). Collectins are collagen-like proteins that bind to carbohydrate or lipid moieties in microbial cell walls. They can have direct microbicidal activity or flag the microbial cell for recognition by the complement system and phagocytosis. They can promote uptake of cells that have undergone apoptosis (cell death without cell disintegration), particularly neutrophils, to avoid release of tissue-toxic constituents [143-148].

The first component of complement, the collectin C1q, is a circulating and cell-associated PRR. It fixes to antibody-coated microorganisms, some unopsonized organisms, immune complexes, apoptotic cells, and DAMPs to initiate the complement cascade and clearance of the organism or particle. But, it is also involved in a broad array of physiologic functions beyond its role in the complement cascade, including a fundamental role in host defense and in preventing autoimmune disease, as demonstrated by the increased frequency of infections and systemic lupus erythematosus (SLE) in individuals who lack C1q [93,149-151]. (See "Complement pathways" and "Inherited disorders of the complement system".)

Mannose-binding lectin (MBL) is an antimicrobial lectin (carbohydrate-binding protein), a well-characterized collectin, and an acute-phase reactant produced by the liver [148,152]. MBL recognizes terminal mannose residues of carbohydrates on gram-positive and gram-negative bacteria, fungi, and some viruses and parasites. MBL can opsonize (from the Greek, "to cater or prepare food for") microbes for phagocytosis and activate the complement pathway, leading to microbial cell lysis, chemoattraction of neutrophils, and phagocytosis. MBL deficiency can be associated with frequent, relatively mild infections in children or immunocompromised adults.

Two of the four pulmonary surfactant proteins (SP-A and SP-D) are collectins that are found in a variety of tissues [153-156]. These proteins bind oligosaccharide PAMPs found on many gram-positive and gram-negative bacteria, viruses, and fungi [144-147,153]. SP-A is expressed in the placental amnion and amniotic fluid, where it may contribute to the amniotic antiinflammatory response during pregnancy [147].

Lectins — Lectins bind carbohydrates, including microbial carbohydrates. MBL is the prototypic host defense lectin, but ficolins 1, 2, and 3 and galectins are other important host defense lectins [157-162]. MBL and ficolins can bind directly to microbes and trigger antibody-independent activation of the lectin pathway, the third of the core pathways of complement activation (with the classical and alternative pathways). There are at least 15 members of the mammalian galectin family. Charcot-Leyden crystals, which characterize severe asthma and rhinosinusitis, are eosinophil-derived crystals of galectin 10 [163]. Some human galectins can bind directly to bacteria, disrupt their membranes, and kill them in the absence of complement. Galectins can inhibit replication of the influenza virus and induce apoptosis of certain cells [160,164,165]. Different galectin family members influence various stages of neutrophil biology, from extravasation, microbiocidal capacity, and turnover. The last is achieved by upregulating surface phosphatidylserine, which promotes clearance of apoptotic neutrophils by macrophages [166]. The lectin RegIII-gamma can kill gram-positive bacteria in the small intestines and has the special property of maintaining a thin zone that physically separates gut microbiota from the small intestinal epithelial surface [167,168].

Pentraxins — Pentraxins are a large family of proteins, highly conserved through evolution and characterized by a C-terminal pentraxin domain with five subunits [169-173]. C-reactive protein (CRP) and serum amyloid P (SAP) are the structurally short-arm family members. Pentraxin 3 (PTX3) is the prototypic "long pentraxin." PTX3, secreted particularly by macrophages and dendritic cells, can bind to endothelial surface P-selectin at sites of inflammation, which blocks neutrophil attachment and recruitment, thereby acting to diminish inflammation as infection is controlled [171]. Pentraxins can bind C1q to trigger the complement cascade and fix the opsonin C3, then interact with complement inhibitors to limit further fixation of complement components [174]. SAP is a constituent of all human amyloid deposits, including those of amyloidosis and Alzheimer disease. Current therapeutic efforts focus on depleting SAP from tissues as a means of treating these two disorders [172].

CRP is an evolutionarily conserved protein and a classic acute-phase reactant, secreted in response to TLR activation or proinflammatory cytokines [175]. It is the first PRR to be described, secreted by the liver, and named for its capacity to react with C-polysaccharide of pneumococci. It functions like an innate, rapidly responsive antibody in that it can fix C1q and activate the complement system, thereby promoting phagocytic clearance. CRP also promotes phagocytosis by directly binding to immunoglobulin G (IgG) Fc-gamma receptors on phagocytes. (See "Acute phase reactants", section on 'Roles of CRP'.)

Cell-associated pattern recognition receptors — Membrane-bound PRRs are expressed constitutively on many types of innate immune cells and on the professional (most active) antigen-presenting cells (macrophages, dendritic cells, monocytes, and B lymphocytes). On all of these cells, transmembrane signaling PRRs act as sentinels. Upon activation, they induce rapid upregulation of other PRRs.

The principal transmembrane and intracellular signal-transducing PRRs are summarized in the table and below (table 2) [176-182]:

Plasma membrane-bound and intracellular TLRs and their associated microbe detection-enhancing proteins (LPS-binding protein, CD14, and MD-2)

C-type lectin receptors (dectins 1 and 2) and macrophage-inducible C-type lectin (MINCLE) on macrophages and dendritic cells

Nucleotide-binding oligomerization domain (NOD) like receptors (NLRs), termed NOD1 and 2

RIG-1-like receptors (RLRs), termed RIG-1 (for retinoic acid-inducible gene 1), melanoma-associated differentiation protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2)

Toll-like receptors — TLRs are transmembrane PRRs that are found on and within cells of the innate immune system (particularly monocytes, macrophages, epithelial cells, and neutrophils), as well as dendritic cells and many other cell types [176-181]. TLRs recognize a variety of PAMPs and DAMPS, including microbial cell wall components, proteins, and nucleic acids (table 3). TLR signaling results in changes in the transcription factors that regulate a multitude of genes, including those encoding important proinflammatory cytokines. The Drosophila protein toll signals resistance to fungi in fruit flies and has a cytoplasmic signaling domain homologous with that of mammalian TLRs [183]. The sea urchin has 222 TLRs, illustrating the importance of these receptors to host defense throughout phylogeny [184]. (See "Toll-like receptors: Roles in disease and therapy".)

Ten human TLRs have been well defined; an 11th has been identified (table 3) [185]. The first identified was TLR4, which is constitutively expressed on many human cell types. TLR4 is specific for and exquisitely sensitive to the presence of bacterial endotoxin (LPS) [186,187]. Picogram amounts of LPS (estimated to equal approximately 10 molecules per cell) are sufficient to stimulate immune cells [188]. The relative protection of the Indiana Amish farming community from asthma is driven by a long-term, low-level proinflammatory innate immune response mediated through TLRs [189,190].

TLRs are homologous with the mammalian interleukin (IL) 1 receptor [191], and they share a MyD88-dependent signaling pathway that induces the transcription factors nuclear factor for the kappa-light chain enhancer in B cells (NFkB) and activating protein 1 (AP-1). These factors transcribe potent proinflammatory cytokines, including tumor necrosis factor (TNF), IL-6, and pro-IL-1-beta.

The central role of TLRs in host defense is demonstrated by experiments of nature in which genetic polymorphisms or mutations are associated with disease. Predisposition to serious viral infections illustrates this point:

Five of the 10 TLRs (TLRs 3, 4, 7, 8, and 9) can trigger production of the type 1 interferons (IFN-alpha, beta, and lambda) that are essential for antiviral immunity. Patients with deficiency of TLR3 [192], UNC93B (the TLR 3, 7, 8, 9 signaling molecule) [193], or signal transducer and activator of transcription (STAT) 1 [194] have suffered severe viral infections, particularly herpes simplex virus-1 encephalitis [195]. (See "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

Hepatocytes express PRRs, including TLRs 2, 3, and 4 and, when challenged by pathogens, can deliver innate immune responses in the liver or by the acute-phase response systemically [196].

Polymorphisms in TLRs have been associated with impaired resistance to respiratory syncytial virus [197] and increased risk of invasive fungal infections [198]. In contrast, a polymorphism in TLR3 confers protection against HIV-1 infection [199].

TLRs are found on cells of both innate and adaptive immune systems, and, although they play a fundamental role in host defense and anti-cancer immunity [200], they have also been reported to contribute to a variety of inflammation-associated pathologic conditions, including cancer, rheumatoid arthritis, psoriasis, diabetes, coronary heart disease, cardiac ischemia, transplant rejection, and asthma [201,202]. (See "Toll-like receptors: Roles in disease and therapy".)

Pattern recognition receptors linked to phagocytosis — Phagocytes express membrane-bound PRRs on their cell surface, which often function in concert with the secreted PRRs. When these cell-surface PRRs bind PAMPs, they initiate phagocytosis, release of toxic oxidants, and delivery of pathogens to phagolysosomes filled with microbicidal products. In macrophages, pathogen-derived proteins are also processed into peptides and presented by cell surface major histocompatibility complex (MHC) molecules to engage and instruct antigen-specific T lymphocytes. (See "Antigen-presenting cells".)

The best studied PRRs found on macrophages include the following (table 2):

The macrophage mannose receptor recognizes carbohydrates with terminal mannan that are characteristic of a variety of microbes, especially fungi [148,203].

Certain members of the macrophage scavenger receptor family can bind bacterial cell walls and trigger phagocytic clearance of the bacteria [204-206].

Dectins 1 and 2 are transmembrane lectin receptors expressed on human macrophages, monocytes, neutrophils, eosinophils, dendritic cells, and lymphocytes [207-209]. Dectin 1 has binding specificity for beta-1,3-glucans, an important component of fungal cell walls. Mutations leading to deficient expression of dectin 1 have been reported in females with recurrent mucocutaneous fungal infections, particularly vulvovaginal candidiasis and onychomycosis [210]. Phagocytosis and killing of fungi by blood leukocytes from these individuals was normal, emphasizing the special role of dectin 1 in defense of skin and mucosa. An autosomal recessive mutation in caspase recruitment-containing domain 9 (CARD9), which is involved in signaling from dectin 1, has been associated with chronic mucocutaneous candidiasis [211]. (See "Chronic mucocutaneous candidiasis", section on 'Dectin-1 deficiency'.)

Another example of a membrane-bound PRR that promotes phagocytosis is the N-formylmethionine (N-fMet) receptor, which is expressed on neutrophils, monocytes, macrophages, and dendritic cells. The amino acid sequence N-fMet initiates all bacterial proteins but only mitochondrial proteins in mammalian cells [212]. Engagement of these bacterial structures by the N-fMet receptor on host immune cells attracts these cells to the bacteria and activates them for phagocytosis and killing.

Intracellular pattern recognition receptors — Intracellular PRRs include some of the TLRs, the NOD-like receptors, and the RIG-1-like receptor family (table 2).

TLRs 3, 7, 8, 9, and 10 reside inside the cell in endolysosomes, membrane-bound compartments that can contain bacterial breakdown products or viruses and digestive enzymes from fused lysosomes. These TLRs recognize nucleic acids derived from viruses and bacteria and stimulate the production of type 1 IFNs (alpha, beta, lambda) and proinflammatory cytokines. (See "Toll-like receptors: Roles in disease and therapy".)

NLRs are intracellular PRRs that sense PAMPS and DAMPs. They are key components of the inflammasome, a multi-protein complex that activates the enzyme caspase 1, which then generates the active forms of the key proinflammatory cytokines IL-1 and IL-18 [213-216]. Caspase 1 protease activity also induces a lytic, proinflammatory form of cell death termed "pyroptosis" ("ptosis" in Greek denotes a falling; "pyro" in Greek is fire, highlighting the context of inflammation).

The relatively well-studied inflammasome components NOD1 and NOD2 recognize different structural core motifs of bacterial peptidoglycans [176,177,180-182,217]. NOD1 recognizes peptidoglycan of all gram-negative bacteria and certain gram-positive bacteria. NOD2 recognizes muramyl dipeptide, a peptidoglycan motif present in all gram-positive and gram-negative bacteria [176,180,217-219]. NOD2 is expressed in monocytes, macrophages, dendritic cells, lymphocytes, epithelial and endothelial cells, and intestinal Paneth cells. TNF-alpha and IFN-gamma can upregulate the NOD2 gene in intestinal epithelial cells [220]. Engagement of either NOD1 or NOD2 activates the transcription factor NFkB, which results in upregulated transcription and production of the proinflammatory mediators. NOD2 has been of particular interest in Crohn disease because three polymorphisms in the NOD2 gene are associated with a 2- to 4-fold risk of this disorder in heterozygotes and an 11- to 27-fold risk in homozygotes [221-223]. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease", section on 'Immune dysregulation and IBD'.)

The RIG-1-like receptor family (RIG-1, MDA5, and LPG2) is a second family of cytoplasmic PRRs. These PRRs recognize the RNA of internalized viruses and mediate production of type-1 IFNs and antiviral immune responses [176,177,181,224].

Genetic defects of PRRs are variable in severity, have a narrow specificity for particular classes of pathogens, and often decrease in severity with age [225].

CELLS OF THE INNATE IMMUNE SYSTEM — A core group of cells plays a primary role in innate immunity. “Professional” phagocytes (neutrophils, monocytes, macrophages, and eosinophils), for example, represent the critical effector component of the innate immune system [226-228]. Dendritic cells express pattern recognition receptors (PRRs) and originate as undifferentiated, innate cell types. As principal antigen-presenting cells, they become the key link between innate and adaptive immunity [229,230].

Neutrophils — Neutrophils, the most abundant circulating phagocytes in humans, are the first cells recruited into sites of infection and inflammation [231]. They are attracted by four major chemotactic factors generated at these sites, and there are specific neutrophil receptors for each. These factors are:

N-formyl bacterial oligopeptide

Complement-derived C5a

Leukotriene B4 (secreted by numerous immune cells)

Interleukin (IL) 8, the neutrophil chemokine secreted by activated innate immune cells and epithelial cells

Certain antimicrobial peptides (AMPs) are also chemotactic for neutrophils [232]. All of these chemoattractants diffuse from the site of infection or injury to provide a chemotactic gradient for neutrophil migration and to further activate neutrophils as they transmigrate. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

Upon reaching the infected site, neutrophils phagocytose invading microorganisms that have been prepared for phagocytosis (opsonized) by innate and acquired immune processes, such as fixation of complement C3 fragments and IgG. Complement receptors 1 and 3 (CR1 and CR3) are the main phagocytic receptors for opsonic C3 fragments [157]. In the presence of antibody to cancer antigens, neutrophils, as well as natural killer (NK) cells and macrophages, can lyse the cancer cell by antibody-dependent cellular cytotoxicity [233]. (See "Complement pathways".)

Following phagocytosis, microbicidal mechanisms kill the ingested microbes almost immediately by merging the microbe-containing phagosome with intracellular granules containing microbicidal products, such as alpha-defensins and highly reactive oxidants generated by the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex (O2-, H2O2, hypochlorous acid, hydroxyl radical) [226,234]. Phagocyte NADPH oxidase has an essential role in killing certain common organisms (eg, staphylococci, enteric bacteria, and Aspergillus), as evidenced by the prominence of infections by these organisms in chronic granulomatous disease (CGD), in which the phagocyte oxidase is deficient [235]. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)

Neutrophil cytoplasmic granule proteases (neutrophil elastase and cathepsin G) are also important to neutrophil microbicidal function. These cationic proteases, rendered inactive in resting cells by component proteoglycans, are solubilized and activated by the conditions in phagocytic vacuoles [236]. Thus, maximal toxicity of these proteases is confined to phagocytic vacuoles, and damage to host tissues is limited.

Neutrophil extracellular traps — As neutrophils crawl toward microbial targets, actin polymerization promotes release of extracellular strands of chromatin decorated with antimicrobial proteins, called neutrophil extracellular traps (NETs) [237,238]. NETs capture and kill microbes and prevent collateral damage by localizing proteases and degrading cytokines and chemokines [239-246]. NETs interact directly with the coagulation system to induce clot formation that can further trap pathogens [247,248]. Mucins and lysozyme in saliva exert antibacterial activity [249], and salivary mucins stimulate release of antimicrobial NETs from salivary neutrophils [244,245]. Saliva from Behçet syndrome patients, who suffer recurrent oral ulcers, does not induce NET formation [244,245]. Macrophages can clear NETs, and this is promoted by the resolvin family of proresolving lipid mediators [250], but, when NETs are elicited by cholesterol crystals, which characterize atherosclerotic plaques, NETs prime the macrophages to release cytokines that drive inflammation [251].

There is evidence to suggest that NET formation can predispose to autoimmune and vasculitic diseases, including rheumatoid arthritis and systemic lupus erythematosus (SLE), as well as diabetes, atherosclerosis, Alzheimer disease, coronavirus disease 2019 (COVID-19) immunothrombosis, muscle damage-induced kidney dysfunction, sepsis injury, acute lung injury after burns, and even cancer [91,252-265]. On the other hand, activation of neutrophils in the acute inflammatory response protects against development of chronic pain [266].

Other components of the neutrophil's potent antimicrobial armamentarium are proinflammatory and can participate in tissue damage when the stimulus is an immune complex or collagen vascular disease or the contents of an arteriosclerotic plaque [267]. Homeostatic balance is restored by tissue DNases that break up the core DNA of the NET [268,269].

Neutrophils are not end-stage cells incapable of modification after leaving the bone marrow, as had been originally thought. Their antimicrobial functions can be markedly upregulated by bacterial products [77]. Neutrophil subsets with different phenotypic properties have been described, and certain neutrophil populations can return to the circulation or migrate into lymph nodes following their initial extravasation [270]. These functions may facilitate inflammation or antigen presentation, respectively.

Neutrophils also express intrinsic stop mechanisms based on sensing the local accumulation of neutrophil-secreted attractants that promote swarming during early stages. When the microbial invaders are contained, these same mechanisms act to desensitize the neutrophils through a negative-feedback mechanism that stops neutrophil migration [271,272].

Monocytes and macrophages — Monocytes develop in the bone marrow and circulate before infiltrating tissues, where they differentiate into either macrophages or dendritic cells [273]. Some pick up antigens and transport them to regional lymph nodes without becoming macrophages [274]. Most serve to renew the resident macrophage population while differentiating into macrophages that are characteristic for the tissue in which they reside (eg, interstitial and alveolar macrophages in the lung, Kupffer cells in the liver, osteoclasts in bone, cardiac macrophages [275,276], and microglia in the brain and retina) [277-283]. This process is accentuated in response to infection or cancer [284-287]. Tissue resident macrophages also arise from yolk sac/fetal liver embryonic progenitors independently of blood monocytes. These and the progeny of monocyte infiltration can self-renew [277-279,284,288]. The generation of foam cells in atherosclerotic plaques results primarily from macrophage proliferation within the plaques [289,290]. It appears that all of these tissue macrophage populations can differentiate into either proinflammatory, microbicidal (M1), or antiinflammatory, pro-healing (M2) subtypes [284,291,292].

There is an array of monocytes, macrophages, and other immune cells in the skull and vertebral bone marrow surrounding the central nervous system (CNS) [293-295]. These cells provide a critical, immediately available reservoir of cells to protect and monitor CNS functioning.

Multinucleated giant cells formed by fusion of macrophages retain their ability to phagocytose and express the metabolic and antimicrobial properties of macrophages [296,297].

Macrophages express a high density of surface PRRs, and, like neutrophils, they respond rapidly to the presence of microbes. These two cell types complement each other and cooperate in effecting innate immunity [227], but they differ in several important ways. Among these, macrophages have an important role in digesting microbes and presenting microbial antigens to lymphocytes to initiate an adaptive immune response to the microbe. In addition, macrophages secrete over 100 proteins that mediate host defense and inflammation, including potent cytokines. They also play an essential role in systemic iron homeostasis, supplying iron for erythropoiesis or sequestering it to prevent iron-dependent bacterial growth [298]. Fetal macrophages contribute to tissue repair that can reduce the risk of premature labor [299,300].

Inflammation is the classic "double-edged sword," and macrophages cut both ways. CNS microglia illustrate this point. These cells evolved to mediate neuronal development [301,302] and to protect the brain from microbial assault, but immune activation in which microglia are key perpetrators is a common feature of neurodegenerative diseases, including Alzheimer and Parkinson diseases, viral encephalopathy, stroke, traumatic brain injury, multiple sclerosis, and loss of cognitive function in the elderly because of air pollution [279,303-309].

Disorders associated with monocytosis or with excessive activation of macrophages are discussed elsewhere. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Eosinophils — Eosinophils release extracellular traps carrying attached eosinophil granules that secrete their contents when stimulated [310,311], and they possess a well-known role in resisting parasitic infection. They are also recognized to be multifunctional cells that phagocytose and kill bacteria and have antiviral activity [312,313]. Eosinophils circulate, but they are primarily resident in the lamina propria of the gastrointestinal tract. They are nurtured there and throughout the body by IL-5, IL-13, and cytokines from immune cells. Unfortunately, their intestinal location allows them to mediate the eosinophilic gastrointestinal diseases (EGIDs; eosinophilic esophagitis, gastritis, enteritis, and colitis) and inflammatory bowel diseases [312,314-319]. In addition, eosinophils and platelets can interact to promote atherosclerotic plaque formation and thrombosis [311], and eosinophil extracellular traps have been shown to drive asthma progression [320].

Mast cells — Mast cells reside in large numbers in the interstitium of peripheral tissues. They express Toll-like receptors (TLRs) 1, 2, 4, and 6; receptors for the complement "anaphylatoxin" C5a; and receptors for mannose-binding lectin (MBL). Upon PRR activation, mast cells release tumor necrosis factor (TNF) alpha and IL-8, which are uniquely preformed in mast cells. These mediators initiate neutrophil infiltration to the site of inflammation [321]. Mast cells also make classic inflammatory mediators (histamine, heparin, leukotrienes, platelet-activating factor), proteases (eg, tryptase, chymase), and AMPs (cathelicidin and defensins) [322-326]. They have immunomodulatory as well as antimicrobial and anti-protozoan functions, and they promote bone metabolism and development and maintenance of alveolar macrophages [325-331]. (See "Mast cells: Development, identification, and physiologic roles" and "Mast cells: Surface receptors and signal transduction" and "Mast cell-derived mediators".)

Basophils — Basophils are leukocytes of myeloid origin that appear only in blood. They express immunoglobulin E (IgE) receptors and are thus primed to participate in the allergic response and resistance to helminth infestation upon release of histamine, cathelicidin, and other mediators. These include IL-4 and IL-13, which promote a lymphocyte T helper type 2 (Th2) response, further enhancing the allergic and antihelminthic response and promoting B cell production of antibody [332,333].

Natural killer cells — NK cells are an innate immune cell type with unique features. They are lymphoid cells that do not express antigen-specific receptors derived from exposure to specific antigens, such as T cell receptors or surface immunoglobulin on B cells. However, NK cells can alter their behavior based on prior exposure to particular antigens, including after viral infection, by a mechanism that is different from that of T and B cells [334-340]. NK cells play an important role in controlling infection by herpesviruses and flaviviruses (eg, Dengue and Zika), and influenza, hepatitis C, human immunodeficiency virus 1 (HIV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses [341].

NK cells express a broad array of activating and inhibitory receptors, including TLRs 2, 3, 4, 5, 7, and 8, and they recognize and respond to the respective TLR ligands directly [336,342,343]. Activating receptors are central to the "killer" function of this cell type, which is to respond to viral infections and malignant tumors by recognizing damaged or "stressed" host cells for elimination. NK cells have granules with perforins and granzymes that, upon activation, are released into the interface between target and effector NK cells, disrupting target cell membranes and inducing apoptosis [344]. NK cells distinguish and avoid healthy host cells through receptors that recognize major histocompatibility complex (MHC) class I molecules expressed on all normal healthy cells [345]. Binding of these receptors inhibits NK cell-mediated lysis and cytokine secretion, whereas deficiency or absence of surface MHC I will target that cell for attack. Since virus-infected and malignant cells often downregulate MHC class I molecules, they become susceptible to attack by NK cells [336,346]. The inhibitory receptors on NK cells are counterbalanced by activating receptors that recognize "stress" ligands expressed on cell surfaces in response to intracellular DNA damage [336]. NK cells play a critically important role in maintaining the balance between protecting the placenta against infection without rejecting the half-foreign fetus [347].

In the give and take between the host and an infecting virus [348], NK cells play a central role, as shown by the serious herpesvirus infections sustained by patients lacking functional NK cells [341,349]. NK cells are reduced in number, metabolically stressed, and functionally deficient in children with obesity, which could relate to the increased rates of cancer in this population [350]. The "immunosenescence" that occurs with aging is regularly associated with a decrease in the number and function of NK cells. Exercise has been experimentally shown to increase the number and cytolytic capacity of NK cells in this population [351]. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Biology of NK cells' and "Immune function in older adults", section on 'Immunosenescence'.)

Three risk factors have been identified for COVID-19: being male, being an older adult, or having an underlying medical condition. However, within other demographic groups, there is large variability in susceptibility to severe COVID-19. Secretion of type 1 interferons (IFNs), IFNs alpha and beta being the prototypes, is central to the antiviral capacity of NK cells. At least some of the variability in severity of COVID-19, including the relative protection of healthy children [352], can be explained by genetic variants or autoantibodies that result in deficient release of type 1 IFNs [353-356]. (See "Toll-like receptors: Roles in disease and therapy", section on 'Severe COVID-19'.)

Innate lymphoid cells — Innate lymphoid cells (ILCs; groups 1 to 3) are a diverse group of lymphocytes found in many tissues, particularly the skin and the mucosal barriers of the lungs and gastrointestinal tract. They develop from the common lymphoid progenitor but do not express antigen receptors or expand into a clone when stimulated [357-363]. Instead, they react quickly to signals from infected or injured tissues by releasing an array of cytokines, including IFN-gamma, IL-5, and IL-17, which direct the immune response to the source of ILC stimulation [364]. Some have cytolytic potential and can act directly to kill tumor cells [365,366]. They limit T cell adaptive responses to intestinal commensal bacteria [367]; continuously produce IL-5, which regulates eosinophil homeostasis [368]; and promote glycosylation of the intestinal epithelial cell surface, which is required to allow survival of the gut microflora but prevent their invasion [369]. Genetic impairment of ILC3 function may be involved in the pathogenesis of Crohn disease [359,370].

Dendritic cells — Dendritic cells, the major antigen-presenting cells, begin life in an immunologically unprogrammed, innate state but serve an essential role in adaptive immunity and represent a key link between the innate and adaptive systems [229,230,281,371-375]. Dendritic cells express branched (dendritic) extensions and endocytic capacity but are heterogeneous from the standpoint of location, surface markers, and level of antigen-presenting activity [281]. As they mature, they develop antigen specificity and thus become an essential component of the adaptive immune system. Dendritic cells capture, process, and present antigens to unprogrammed T cells in order to induce adaptive immunity or tolerance to self-antigens. The functions of dendritic cells and other antigen-presenting cells are reviewed in more detail elsewhere. (See "Antigen-presenting cells".)

The mechanism by which endotoxin and other pathogen-associated molecular patterns (PAMPs) enhance the adaptive immune response to antigen (eg, act as adjuvants) involves the potent induction of IL-12 and type 1 IFNs alpha and beta by the antigen-presenting dendritic cells and macrophages [376,377]. These mediators are key regulators of dendritic cell development and the T helper type 1 (Th1) immune response that is essential to host defense.

Dendritic cells that have migrated into lymphoid organs and peripheral sites of the dendritic cell network internalize microbial products (lipopolysaccharide [LPS] and other PAMPs that bind to PRRs), molecules released from damaged tissue (damage-associated molecular patterns [DAMPs], "danger signals" or "alarmins"), some tumors, or self-antigens [378,379]. This "innate" step induces dendritic cell maturation, which is accompanied by upregulation of cytokine receptors, the MHC class II, and the costimulatory molecules CD80 and CD86.

Dendritic cell subtypes express different PRRs, but all possess various TLRs [380]. Once matured, dendritic cells present antigen to unprogrammed T lymphocytes and induce their proliferation. These effector T lymphocytes actively secrete IFN-gamma, which, in a positive feedback relationship, further primes the dendritic cells to produce greater amounts of IL-12 in response to stimulation [381,382]. IFN-gamma also activates macrophages to a more effective microbicidal state. Defects in the IFN-gamma/IL-12 mechanism resulting in immunodeficiency are discussed separately. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

Other cells that contribute to innate immunity — Primary innate immune cells are not the only cells that participate in innate host defense [383]. Additional cell types with other primary physiologic functions also express PRRs and TLRs and contribute importantly to innate immunity. However the cells might be classified, their distribution throughout the body's organ systems emphasizes the essential nature of innate immunity for development and survival across the species.

Epithelial and endothelial cells – As a fertilized egg becomes an embryo, organ development must be contained within some form of protective covering, a requirement for embryogenesis and life thereafter. In the mature animal, skin and mucous membranes, comprised of epithelial and endothelial cells, serve this function. Beyond this fundamental role, epithelial and endothelial cells also contribute prominently to host defense.

Like macrophages, these cells reside in tissue areas of high antigenic exposure and express PRRs that allow them to recognize PAMPs and respond even more quickly than neutrophils and monocytes do. Epithelial cells provide a continuous physical barrier, as well as clearance mechanisms (eg, mucociliary system and surfaces coated with AMPs) to protect the host from the external environment. Human airway epithelial cells express multiple TLRs and, when PAMP stimulated, produce proinflammatory cytokines, including IL-8 [384] and AMPs [385]. Human skin keratinocytes express a mannose-binding receptor that mediates killing of Candida [386], and they release multiple AMPs [387]. Paneth cells, specialized epithelial cells at the base of intestinal crypts, secrete lysozyme and other AMPs during intestinal infection [388]. In the gastrointestinal tract, TLR-mediated epithelial responses to the PAMPS of commensal bacteria promote epithelial integrity and resilience to injury [389]. In response to IFN-gamma, epithelial and endothelial cells and fibroblasts produce apolipoprotein L3 (APOL3), an intracellular protein that can dissolve the cell membranes of cytosolic bacteria [14]. On the other hand, signaling through TLRs on amniotic epithelial cells leads to release of cytokines that can provoke preterm labor [390].

Goblet cells – Intercrypt goblet cells in the colon are high-output mucus secreters that are essential for the colon's mucus barrier function [391]. Defects in this barrier characterize colitis.

Tuft cells – Bitter taste receptors in the upper respiratory tract can protect against toxic compounds, including bacterial products from spoiled food. They also protect against infection by responding to bacterial products with vigorous release of AMPs [392]. Tuft cells are specialized epithelial cells in the linings of the intestines, lungs, nasal passages, pancreas, gallbladder, thymus, and urethra. They display taste receptors in most locations. These cells serve as innate sentinels along the body's invasion routes that detect pathogens and allergens and help coordinate antimicrobial responses, with a particularly important role in rejecting parasites [393,394].

Megakaryocytes – Megakaryocytes, which give rise to platelets, secrete IFNs alpha and beta and express intrinsic antiviral immunity [395,396].

Platelets – Platelets are well known for their role in hemostasis, but they also play a remarkable role in host defense, wound repair, and resolution of the inflammatory process [397-405]. They express PRRs that can directly bind pathogens; produce cytokines; recruit leukocytes to sites of infection or tissue damage; interact with leukocytes and endothelial cells through P-selectin to mediate proinflammatory events [397,406], including the killing of malaria parasites and staphylococci; influence brain function; and act as mediators of brain function [399,400,407,408]. Their roles in mediating inflammation are important in pathologic conditions, such as atherosclerosis, sepsis syndrome, and neurologic diseases [401,402,408-410].

Erythrocytes – Red cells modulate innate immunity by binding and scavenging circulating chemokines, nucleic acids, and pathogens [411-413].

Alpha-intercalated cells – These cells in the collecting duct of the kidney are essential for maintaining acid-base balance. They also defend against upper and lower urinary tract infection by binding uropathogenic E. coli and then acidifying the urine and secreting the bacteriostatic protein lipocalin 2 [128].

Hepatocytes – Hepatocytes express PRRs, including TLRs 2, 3, and 4, and, when challenged by pathogens, can deliver innate immune responses in the liver or systemically through the acute-phase response. Hepatocytes play a direct role in the innate defense against hepatitis C and hepatitis B viruses [196]. The efferent vagal pathway of the CNS connects with acetylcholine receptors on immune cells in the spleen and liver, suppressing cytokine release and inflammation [414-416].

Adipocytes – Adipocytes (fat cells) in lean tissue act as a dynamic endocrine organ that secretes adipokines to coordinate the intake, utilization, and storage of nutrients [417,418]. Leukocytes that traffic to and reside in lean adipose tissue are believed to contribute to this control [419,420]. Adipocytes in obese visceral tissue are enlarged, and their associated immune cells release proinflammatory mediators, including TNF-alpha, IFN-gamma, and IL-1, which are believed to inhibit insulin action and promote metabolic syndrome, type 2 diabetes, cardiovascular disease, and systemic inflammation [418-424]. However, adipocytes also participate in host defense by producing the AMP cathelicidin, which kills the staphylococci [425].

HOMEOSTASIS IN THE INNATE IMMUNE SYSTEM — Although humans exist day-to-day in a hostile microbe-laden environment, we are normally unaware of the constant battles waged to prevent harmful infection. For those with a normal immune system, signs of infection-induced inflammation are relatively uncommon, and, when they appear, they disappear as soon as the battle is over. This potent but unapparent immune protection of the well-defended host is a reflection of the quiet efficiency of front-line defenses (eg, antimicrobial peptides [AMPs], complement, and phagocytes) combined with active homeostatic processes within the innate immune system that regulate and limit inflammatory responses. In sum, microbe-induced activation of the innate immune system is tightly linked to the concurrent induction of downregulatory mechanisms to regain immune homeostasis. A few examples illustrate this point:

Macrophages are essential for host defense, but they also play a central role in maintaining immune homeostasis. For example, engagement of pathogen-associated molecular patterns (PAMPs) with macrophage pattern recognition receptors (PRRs) primes pulmonary alveolar macrophages for antimicrobial activity, but, as the infection clears, these cells actively suppress dendritic cell maturation, antigen presentation, and function in adaptive immunity [426-428]. Activation of macrophages induces not only proinflammatory antimicrobial responses but also the antiinflammatory mediators, interleukin (IL) 10, transforming growth factor (TGF) beta, and prostaglandin E2 (PGE2), which downregulate macrophage and dendritic cell functions.

There appear to be subtypes of neutrophils [429]. One of these promotes vascularization [430,431], and another inhibits T cell responses [432].

Eosinophils contribute to tissue remodeling and repair [433], induction of dendritic cell activation and adaptive immunity, maintenance of immunoglobulin A (IgA) expressing plasma cells, and other regulatory functions [434].

During the early stages of inflammation, endothelial cells and neutrophils release specialized proresolving mediators (resolvins, protectins, and maresins), which enhance clearance of bacteria and apoptotic/necrotic cells, decrease release of macrophage proinflammatory cytokines, accelerate clearance of acute inflammation, and suppress tumor growth [435,436]. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are substrates for synthesis of these agents through a process involving cyclooxygenase 2 (COX-2) [437-442]. COX-2 inhibitors, such as celecoxib, inhibit release of resolvins, perhaps explaining in part the deleterious effect of COX-2 inhibitors in acute infectious inflammation and, over time, cardiovascular disease. In contrast, atorvastatin promotes synthesis of resolvins, which could play a role in the antiinflammatory effect of statins [437,443,444]. EPA and DHA from fish oil displace membrane arachidonic acid, the source of bronchoconstrictive leukotrienes. In one study, pregnant females given fish oil in the third trimester delivered offspring who had one-third the rate of persistent wheezing or asthma over a five-year period compared with offspring of a control group given olive oil [445-448]. Other studies have found less dramatic effects. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy", section on 'Marine omega-3 fatty acid supplements and fortified foods'.)

Efferocytosis — Efferocytosis (Latin for "to take to the grave" or "to bury") is a remarkable example of homeostasis within the innate immune system. The term refers to the uptake and processing of apoptotic (dead but relatively intact) cells by macrophages and dendritic cells [449-451]. In a normal adult, approximately 100 billion neutrophils leave the marrow, circulate, enter tissues, and die each day, even in the absence of acute infection [452]. Cells become senescent and die in all tissues, particularly as the body ages [453,454].

Apoptotic cells and autolyzed, necrotic neutrophils release cytotoxic, proinflammatory constituents (damage-associated molecular patterns [DAMPs]) into their environment, promoting tissue damage and disease, as in arthritis, arteriosclerosis, inflammatory bowel disease, and coronavirus disease 2019 (COVID-19) [455]. The body counters with a constitutive antiinflammatory process of apoptotic cell recognition and ingestion. The constant turnover of dying cells, particularly neutrophils, would be potently inflammatory without the process of efferocytosis. Phagocytic removal of apoptotic cells prevents release of their toxic constituents by necrosis, thereby reducing the risk of inflammation. Moreover, this process shifts macrophage and epithelial cell cytokine release from proinflammatory to antiinflammatory, further moving the process toward resolution [440,456-460]. Thus, efferocytosis is central to the successful resolution of inflammation [450,458,459,461,462]. As humans age, efferocytosis becomes less efficient, resulting in persistent inflammation and decreased resistance to infection [453,454]. Although macrophages have received most of the attention in mediating efferocytosis, other cell types can perform the same function, including epithelial and endothelial cells, fibroblasts, and stromal cells.

Macrophages recognize apoptotic cells through molecular patterns, reminiscent of microbial recognition by innate immune cells. The plasma membrane of viable cells actively maintains an asymmetric phospholipid distribution such that phosphatidylserine is kept on the inner side of the membrane bilayer. Apoptosis perturbs this asymmetry and exposes phosphatidylserine on the cell's outer surface, leading to its recognition by macrophages bearing phosphatidylserine receptors [463-465]. Upon recognition of apoptotic cells, macrophages release antiinflammatory IL-10, PGE2, and TGF-beta to complete the task of maintaining immune homeostasis. In turn, the apoptotic process in monocytes and macrophages themselves is regulated by a complex network of differentiation factors and inflammatory stimuli that determine their lifespan and thus their participation in the yin-yang of host defense [466].

The pathogenicity of some bacteria depends on their release of cytotoxins that induce phagocyte necrosis and temporarily overwhelm efferocytosis [467]. High-mobility group box 1 (HMGB1), a DNA-binding nuclear protein released from disrupted cells, is a potent mediator of inflammation through its capacity to diminish phagocytic uptake of apoptotic cells [468]. HMGB1 can disrupt bacterial biofilms, although this also promotes inflammation [469].

Clearance of necrotic cells and cell debris involves some of the same "find me" and "eat me" signals and phagocytic cell receptors central to removal of apoptotic cells, but the process differs in important ways, including the signals and receptors employed [470]. The complement component C1q and the collectins, mannose-binding lectin (MBL) and surfactant proteins (SP-A and SP-D), can bind apoptotic and necrotic cells and mediate their clearance [470,471]. Individuals with genetic C1q deficiency commonly present with autoimmunity, which is hypothesized to be due at least partly to deficient phagocytic clearance of apoptotic cells [470,472,473]. (See "Inherited disorders of the complement system", section on 'C1 deficiency'.)

Defects in immune homeostasis — Individuals with chronic granulomatous disease (CGD) suffer severe bacterial and fungal infections but also various inflammatory disorders, such as sterile inflammation and inflammatory bowel disease [474,475]. This apparently contradictory combination of problems has been attributed to the dual functions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is defective in the neutrophils and macrophages of patients with this disease. Infections result from defective NADPH oxidase-dependent, phagocytosis-associated generation of microbicidal oxygen metabolites, such as hydrogen peroxide. Excessive inflammation is attributed to a defect in the regulation of inflammation by NADPH oxidase, and studies with murine and human CGD phagocytes show failure during phagocytosis to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox-sensitive antiinflammatory regulator [476]. In addition, CGD macrophages do not ingest apoptotic neutrophils normally [477]. This can be reversed by exposure of the macrophages to the key macrophage activator interferon (IFN) gamma, which is used in the treatment of CGD [478]. (See "Chronic granulomatous disease: Treatment and prognosis".)

INTERACTION OF INNATE AND ADAPTIVE IMMUNITY — When the concept of innate immunity was initially developed, the emphasis was on the emergence of certain immune mechanisms early in evolution and how these mechanisms function without needing prior experience with the microbe or the help of T or B lymphocytes. However, as the field progressed, pattern recognition receptors (PRRs) were recognized on cells of the adaptive system as well, demonstrating that the innate and adaptive immune systems interact at many points and enhance each other's function [479-482].

Innate immunity instructs adaptive immunity — The adaptive immune system has a potentially limitless repertoire of antigen receptors, but innate mechanisms help to focus adaptive responses on pathogens rather than on harmless environmental antigens or self-antigens. Examples include the following.

Role of pattern recognition receptors — The interaction between pathogen-associated molecular patterns (PAMPs) and PRRs is central to the function of the innate immune system, but it also controls the activation of adaptive immune responses by directing microbial antigens through the cellular processes that lead to presentation to T and B lymphocytes [201,202,479-485].

Endotoxin (lipopolysaccharide [LPS]), a PAMP that makes up most of the outer membrane of gram-negative bacteria, is a powerful adjuvant in the induction of antigen-specific T cell memory [480,481,483]. Specifically, vaccination with protein antigen alone results in a short-lived proliferative response of B and T lymphocytes. However, a very different response ensues if endotoxin is included with the antigen, which more accurately reflects the way the human body would encounter most microbial antigens in nature. Including adjuvant with a vaccine results in a long-lived response from effector T cells, a persistent antibody response, and the development of immunologic memory [484,485]. Protection against whooping cough by the acellular pertussis vaccine is proving to be shorter lived than that of whole cell vaccine, which contained large amounts of endotoxin. At least with some antigens, collaboration between the innate and adaptive systems gives the optimally protective immune response.

Innate immune PRRs, particularly Toll-like receptors (TLRs) 2 and 4, also recognize and expedite the removal of damage-associated molecular patterns (DAMPs) or "alarmins" that are released from host cells as a result of infection or tissue injury (see 'Damage-associated molecular patterns' above). Once released extracellularly, alarmins can activate innate immune cells to release proinflammatory cytokines that can lead to shock, organ failure, and sepsis syndrome [91,92,379,486,487]. Complicating the management of these life-threatening clinical conditions, a compensatory antiinflammatory response syndrome (CARS) occurs alongside the proinflammatory response, blunting the host defense capacity of the innate immune system [488,489]. When the compensatory response is severe, "immunoparalysis" occurs, affecting both innate and adaptive immunity [490]. Alarmins can enhance the adaptive immune response, however, through their stimulation of dendritic cells, thus serving to link innate immunity to the adaptive arm of the immune response.

Role of innate immune cells — Neutrophils, macrophages, natural killer (NK) cells, and other cells of the innate immune system feature PRRs that recognize microbial antigens and stimulate a direct antimicrobial response. But these cells also promote antigen-specific adaptive immunity through various means as they work to directly eliminate invaders. (See 'Cells of the innate immune system' above.)

Dendritic cells function as a direct link between innate and adaptive immunity, with the capacity to ingest foreign antigens through PRRs and then to process and present their products to T and B lymphocytes. (See 'Dendritic cells' above.)

Innate immune NK cells, macrophages, and dendritic cells contribute to direct control of viral replication and induce viral-specific adaptive immune responses (antibody and cytotoxic T cells). For example, influenza virus initiates rapid differentiation of monocytes into dendritic cells that produce interferons (IFNs) alpha and beta, which in turn contribute to the innate antiviral response [491].

Neutrophils can form networks with dendritic cells and NK cells that upregulate NK cell release of IFN-gamma [492], which can then activate macrophages and thereby enhance T cell-dependent, cell-mediated immunity. Although studies suggest that a subset of neutrophils can inhibit T cell responses [432], neutrophil extracellular traps (NETs) can prime T cells so that they respond more effectively in antigen processing [493].

Role of antimicrobial proteins and peptides — Antimicrobial proteins and peptides (AMPs) protect the skin and mucosal surfaces and participate in the killing of phagocytosed organisms (see 'Antimicrobial peptides' above). Beyond this first-line, rapid-response function, these molecules support the development of an adaptive immune response to the threatening organisms in several ways [494-498]:

AMPs serve as chemoattractants for adaptive immune cells, as well as for neutrophils and monocytes. Recruitment of dendritic cells by AMPs induces their maturation. Human alpha-defensins attract immature dendritic cells and peripheral blood CD4 and CD8 T cells, thereby enhancing antigen-specific adaptive immune responses [494].

Human beta-defensin-2 can enhance IFN-gamma release from blood T cells [495].

In vitro studies show that human LL-37 stimulates dendritic cells to express increased endocytic capacity, modified phagocytic receptor function, upregulation of costimulatory molecules, enhanced secretion of T helper type 1 (Th1) inducing cytokines, and enhanced Th1 responses [496].

The beta-defensins and LL-37 are chemoattractive for mast cells and can induce their degranulation [497,498]. Mediators in mast cell granules can affect adaptive immunity by modifying dendritic cell function [499]. (See "Mast cells: Development, identification, and physiologic roles", section on 'Innate immunity'.)

Adaptive immunity enhances innate immunity

Amplification of host defense also goes in the direction of adaptive to innate. Dendritic cells recruit, interact with, and activate NK cells through cytokines (eg, type I IFNs, IL-12, IL-18) and cell-to-cell surface interactions [336,500,501].

Opsonization of encapsulated bacteria by complement fragments facilitates phagocytosis by cells bearing complement receptors, such as neutrophils and mononuclear phagocytes. However, even in the presence of a fully active innate complement system, clearance of heavily encapsulated bacteria, such as pneumococci, is ineffective in the absence of antibody, as evidenced by the serious infections sustained by individuals with hypogammaglobulinemia. (See "Complement pathways", section on 'Biologic functions of complement'.)

Macrophages can ingest mycobacteria during their first encounter, but they cannot kill them effectively unless activated by IFN-gamma, a cytokine released from T cells that have been programmed by exposure to mycobacterial antigens.

INTEGRATION OF INNATE IMMUNITY INTO PHYSIOLOGIC SYSTEMS — Survival against infection was a major driver of evolution. The individual cells that participate in innate immunity are described above. As organ-specific and general body systems of human physiology evolved, many incorporated elements of host defense. Examples are described below.

Integration with nervous system functions — Both clinicians and the general public have long recognized that mental and physical health are interrelated in what is commonly referred to as the "mind-body connection." Research has indicated emotional health and a positive emotional style favor cardiovascular health, accelerated recovery from infection, and resistance to colds and to respiratory infection after controlled nasal inoculation of rhinovirus or influenza virus [502,503].

The central nervous system (CNS) and the immune system had been thought to act independently until recently. It is now clear that there is highly organized communication between the two systems that preserves homeostasis in health and disease [504-506]. The CNS communicates with the immune system through hormonal and neural pathways: sympathetic, parasympathetic, and enteric [507]. The immune system influences the CNS and protects it through cytokines from activated immune cells in the periphery, activated microglia and astrocytes in the spinal cord and brain, and other immune cells that exist in the bone marrow around the skull [295,508-510]. Neuro-immune crosstalk plays a key role in the pathophysiology of allergic disease and asthma [511]. Pre-coronavirus disease 2019 (COVID-19) infection psychological stress (depression, anxiety, loneliness, worry about COVID-19 infection) has been reported to increase the risk of long COVID-19 by up to 50 percent [512]. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

Stimulation of the brain's reward system in mice resulted in upregulation of innate immune cell receptors, including Toll-like receptor (TLR) 4, increased phagocytosis and killing of E. coli by macrophages, and increased adaptive immune response [513,514]. The reward system's effects were mediated at least partially by the sympathetic nervous system, which extends from the brain into the spleen and other lymphoid organs. These responses to a perceived reward may also play a part in the placebo effect. If the sympathetic nervous system is activated by stress, release of neurotransmitters like noradrenaline can suppress immune responses through effects on the vasculature that impede leukocyte migration [507,515].

The efferent vagal pathway of the CNS connects with cholinergic receptors on immune cells in the spleen and liver, suppressing cytokine release and inflammation [414-416,516]. This and other examples of the neuronal inflammatory reflex illustrate the central and essential role that neuronal signals play in regulating the immune response [415,416]. In fact, each of the four classic signs of inflammation, dolor (pain), calor (heat), tumor (swelling), and rubor (redness), are primarily due to neuronal activation.

The complement system and microglia, the brain's macrophages, are active in brain host defense and in clearing debris and promoting healing after traumatic brain injury [517,518]. Microglia are also essential to normal brain development because they prune weakly active, unnecessary synapses to allow more active synapses to develop during normal brain maturation. This pruning process is guided by tagging of the superfluous synapses by C1q and the complement system. Microglia then phagocytose tagged synapses through their complement receptors [519]. Data also indicate that, during development, microglia orchestrate construction and regulation of neural networks that function in the adult brain [301,302].

Not unexpectedly, however, microglia and complement can play a central role in brain disease, including autism and Alzheimer disease [520]. As humans age, brain C1q levels rise dramatically, and they may drive neurodegenerative disease and cognitive decline through the complement recognition mechanism [521]. Serum C1q levels also rise steeply with aging as a reflection of muscle loss; levels can be returned to baseline by a program of resistance exercise [522], raising the interesting possibility that resistance exercise could reduce unwanted inflammation by reducing available C1q. At least in mice, complement-dependent synapse elimination by microglia underlies the normal forgetting of remote memories [523,524]. Some individuals with heritable schizophrenia have greater expression in the brain of complement component C4A, perhaps explaining the cortical thinning and reduced numbers of synaptic structures characteristic of this disorder [525,526]. Dysfunction of innate immune signaling pathways required for responses through TLRs, cytokines, and phagocytic engagement, has been linked to many developmental disorders, including autism and schizophrenia [527].

Variation in expression of innate immune components in the cerebellum and cerebral cortex, brain areas that evolved separately, appears to permit infection by herpes simplex virus specifically in the cortex and infection by West Nile virus in the cerebellum [528].

Substance P is a peptide neurotransmitter secreted by sensory neurons. Its receptor is distributed over many cell types and tissues, and it can modulate immune cell proliferation, cytokine release, and inflammation. It shares physical and chemical properties with antimicrobial peptides (AMPs) and has direct antimicrobial activity [529,530].

A systematic review and metanalysis of 56 randomized controlled trials with 4060 participants analyzed the effect of eight psychosocial interventions on seven immune outcomes [531]. Psychosocial interventions, particularly cognitive behavioral therapy, significantly reduced proinflammatory markers and increased beneficial immune functions, with changes lasting at least six months after completion of therapy.

Integration into other systems

C1q is involved in a broad array of physiologic functions beyond its role in complement activity. Besides synapse pruning, these include dendritic cell development, apoptotic cell clearance, placental development, and cell metabolism [95,150,151].

Metabolism and immunity have been interwoven since the emergence of life [532,533]. The role of proinflammatory cytokines, particularly of macrophage origin, in insulin resistance, obesity, and diabetes was established in the 1990s, and later work indicates that the metabolic state is a critical determinant of immune function. Current experimentation in the field of immunometabolism targets possible interventions to disrupt interactions at the basis of chronic disease, particularly obesity [534].

Coagulation factor XIII cross-links fibrin and bacteria and then exerts direct antimicrobial activity [535,536]. In another example of coevolution, clotting factor X coats circulating common cold adenoviruses and targets them to TLR4 on macrophages, with resultant production of proinflammatory cytokines that can contribute to eventual removal of the virus [537,538]. Moreover, secretory products from phagocytic leukocytes (granule enzymes, cytokines) and damage-associated molecular patterns (DAMPs) can influence all aspects of thrombosis [539,540]. (See "Toll-like receptors: Roles in disease and therapy".)

Proteins of the innate immune system with both antimicrobial and antiinflammatory potential attach to high-density lipoprotein (HDL) cholesterol [541,542].

Studies in mice show that each cardiac muscle cell touches an average of five cardiac macrophages. To function normally, muscle cells eject spent mitochondria and muscle proteins in small packets called exophers. If exophers are not cleared by macrophages, dysfunctional mitochondria accumulate in the muscle cells, and ventricular function is impaired [275,276].

The pervasive distribution of host defense immune capacity and its attendant inflammation, essential to survival through the reproductive period, can over time also contribute to the pathogenesis of organ-specific diseases (eg, Alzheimer disease and other neurodegenerative diseases) [285,287,289,303,306,521], autoimmune disease (such as chronic active hepatitis), cancer, or atherosclerosis. Better understanding of these various interactions could allow improved therapeutic interventions.

SUMMARY

Definition – Innate immunity refers to a system of rapid immune responses, inherited from parents and present at birth, which are a first-line defense against invasion by microbes and infection. The innate immune system activates and instructs adaptive immune responses, regulates inflammation, and mediates immune homeostasis (the balance between opposing proinflammatory and antiinflammatory processes). (See 'Critical functions' above.)

Components – Components of the innate immune system include those of the host itself, as well as those of its resident microbes, the microbiome. Host components include physical barriers, many different cell types, various receptors and sensors such as inflammasomes, and cytokines. (See 'Components of innate immunity' above.)

Pattern recognition receptors – Cells of the innate immune system use pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) on microorganisms. PRRs also recognize and direct removal of components of damaged tissue (damage-associated molecular patterns [DAMPs]) (table 1 and table 2). PRRs do not undergo gene rearrangement to become highly specific receptors for particular antigens, as antigen receptors on T and B lymphocytes do. However, innate immune responses can be "trained" through epigenetic changes to express enhanced responses to the original pathogen and also to unrelated microbes. In addition, components of innate immunity are refined over generations by evolutionary pressures. (See 'Microbial detection through pattern recognition' above and 'Training of innate immunity' above.)

Activation at the site of insult – Activation of the innate immune system begins with resident cells in the tissues at the site of the insult (macrophages, epithelial cells, mast cells, innate lymphoid cells [ILCs]). If the threat of infection accelerates, these cells release cytokines to recruit other cells (neutrophils, natural killer [NK] cells, dendritic cells, monocytes, platelets) from the circulation into the inflamed tissues. (See 'Cells of the innate immune system' above.)

Instruction of adaptive immune responses – The cells and circulating factors of the innate immune system represent a potent first line of defense, but they cannot function optimally without the specific antibodies and sensitized T cells that effect adaptive immunity. The innate immune system communicates directly, cell-to-cell, with adaptive immune cells and releases mediators that activate and instruct the adaptive immune system. In these ways, innate immune mechanisms enhance and instruct antigen-specific T and B lymphocyte responses and the development of immunologic memory. (See 'Innate immunity instructs adaptive immunity' above.)

Control of inflammation and homeostasis – Many of the same cells and mechanisms that act to recognize and attack microbes and initiate inflammatory reactions also clear away damaged and dying cells and their cell components then downregulate inflammation to maintain homeostasis within the host. (See 'Homeostasis in the innate immune system' above.)

Integration into physiologic systems – As basic physiologic systems evolved, some incorporated functions of the innate immune system to contribute to their defense or to amplify their primary role in physiology. (See 'Integration of innate immunity into physiologic systems' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

  1. Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989; 54 Pt 1:1.
  2. Medzhitov R, Janeway CA Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997; 91:295.
  3. Medzhitov R. Pattern recognition theory and the launch of modern innate immunity. J Immunol 2013; 191:4473.
  4. Travis J. Origins. On the origin of the immune system. Science 2009; 324:580.
  5. Boller T, He SY. Innate immunity in plants: an arms race between pattern recognition receptors in plants and effectors in microbial pathogens. Science 2009; 324:742.
  6. Hoffmann J, Akira S. Innate immunity. Curr Opin Immunol 2013; 25:1.
  7. Jones JD, Vance RE, Dangl JL. Intracellular innate immune surveillance devices in plants and animals. Science 2016; 354:6316.
  8. Colonna M. Editorial Overview: Sense and react: how the innate immune system detects threats and generates protective responses. Curr Opin Immunol 2017; 44:v.
  9. Gao LA, Wilkinson ME, Strecker J, et al. Prokaryotic innate immunity through pattern recognition of conserved viral proteins. Science 2022; 377:eabm4096.
  10. Spadoni I, Zagato E, Bertocchi A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 2015; 350:830.
  11. Bouziat R, Jabri B. IMMUNOLOGY. Breaching the gut-vascular barrier. Science 2015; 350:742.
  12. Birchenough GMH, Johansson MEV. Forming a mucus barrier along the colon. Science 2020; 370:402.
  13. Bergstrom K, Shan X, Casero D, et al. Proximal colon-derived O-glycosylated mucus encapsulates and modulates the microbiota. Science 2020; 370:467.
  14. Gaudet RG, Zhu S, Halder A, et al. A human apolipoprotein L with detergent-like activity kills intracellular pathogens. Science 2021; 373.
  15. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med 2020; 383:2255.
  16. Hinde K, Lewis ZT. MICROBIOTA. Mother's littlest helpers. Science 2015; 348:1427.
  17. Patel RM, Denning PW. Intestinal microbiota and its relationship with necrotizing enterocolitis. Pediatr Res 2015; 78:232.
  18. Blaser MJ. The microbiome revolution. J Clin Invest 2014; 124:4162.
  19. Relman DA. The Human Microbiome and the Future Practice of Medicine. JAMA 2015; 314:1127.
  20. Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature 2016; 535:65.
  21. Lynch SV, Pedersen O. The Human Intestinal Microbiome in Health and Disease. N Engl J Med 2016; 375:2369.
  22. Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 2016; 22:1079.
  23. O'Dwyer DN, Dickson RP, Moore BB. The Lung Microbiome, Immunity, and the Pathogenesis of Chronic Lung Disease. J Immunol 2016; 196:4839.
  24. Jiang TT, Shao TY, Ang WXG, et al. Commensal Fungi Recapitulate the Protective Benefits of Intestinal Bacteria. Cell Host Microbe 2017; 22:809.
  25. Gilbert JA, Blaser MJ, Caporaso JG, et al. Current understanding of the human microbiome. Nat Med 2018; 24:392.
  26. Blander JM, Longman RS, Iliev ID, et al. Regulation of inflammation by microbiota interactions with the host. Nat Immunol 2017; 18:851.
  27. Neil JA, Cadwell K. The Intestinal Virome and Immunity. J Immunol 2018; 201:1615.
  28. Stiemsma LT, Michels KB. The Role of the Microbiome in the Developmental Origins of Health and Disease. Pediatrics 2018; 141.
  29. McDonald B, McCoy KD. Maternal microbiota in pregnancy and early life. Science 2019; 365:984.
  30. Lazzaro BP, Zasloff M, Rolff J. Antimicrobial peptides: Application informed by evolution. Science 2020; 368.
  31. Harris-Tryon TA, Grice EA. Microbiota and maintenance of skin barrier function. Science 2022; 376:940.
  32. Surana NK, Kasper DL. Deciphering the tête-à-tête between the microbiota and the immune system. J Clin Invest 2014; 124:4197.
  33. Torow N, Hornef MW. The Neonatal Window of Opportunity: Setting the Stage for Life-Long Host-Microbial Interaction and Immune Homeostasis. J Immunol 2017; 198:557.
  34. Gray LE, O'Hely M, Ranganathan S, et al. The Maternal Diet, Gut Bacteria, and Bacterial Metabolites during Pregnancy Influence Offspring Asthma. Front Immunol 2017; 8:365.
  35. Gaufin T, Tobin NH, Aldrovandi GM. The importance of the microbiome in pediatrics and pediatric infectious diseases. Curr Opin Pediatr 2018; 30:117.
  36. Zhang D, Frenette PS. Cross talk between neutrophils and the microbiota. Blood 2019; 133:2168.
  37. Fragkou PC, Karaviti D, Zemlin M, Skevaki C. Impact of Early Life Nutrition on Children's Immune System and Noncommunicable Diseases Through Its Effects on the Bacterial Microbiome, Virome and Mycobiome. Front Immunol 2021; 12:644269.
  38. Harrison O. Poised for tissue repair. Science 2020; 369:152.
  39. Nakatsuji T, Chen TH, Narala S, et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med 2017; 9.
  40. Nakatsuji T, Hata TR, Tong Y, et al. Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial. Nat Med 2021; 27:700.
  41. Tuganbaev T, Yoshida K, Honda K. The effects of oral microbiota on health. Science 2022; 376:934.
  42. Nishida K, Sawada D, Kuwano Y, et al. Health Benefits of Lactobacillus gasseri CP2305 Tablets in Young Adults Exposed to Chronic Stress: A Randomized, Double-Blind, Placebo-Controlled Study. Nutrients 2019; 11.
  43. Zhang P, Wu X, Liang S, et al. A dynamic mouse peptidome landscape reveals probiotic modulation of the gut-brain axis. Sci Signal 2020; 13.
  44. Pennisi E. Meet the psychobiome. Science 2020; 368:570.
  45. Gershon MD, Margolis KG. The gut, its microbiome, and the brain: connections and communications. J Clin Invest 2021; 131.
  46. Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest 2014; 124:4212.
  47. Seekatz AM, Young VB. Clostridium difficile and the microbiota. J Clin Invest 2014; 124:4182.
  48. Dalal SR, Chang EB. The microbial basis of inflammatory bowel diseases. J Clin Invest 2014; 124:4190.
  49. Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 2014; 124:4204.
  50. Grigg JB, Sonnenberg GF. Host-Microbiota Interactions Shape Local and Systemic Inflammatory Diseases. J Immunol 2017; 198:564.
  51. Yan H, Baldridge MT, King KY. Hematopoiesis and the bacterial microbiome. Blood 2018; 132:559.
  52. Hagan T, Cortese M, Rouphael N, et al. Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans. Cell 2019; 178:1313.
  53. Chang JT. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med 2020; 383:2652.
  54. Blaser MJ. Fecal Microbiota Transplantation for Dysbiosis - Predictable Risks. N Engl J Med 2019; 381:2064.
  55. Gurram B, Sue PK. Fecal microbiota transplantation in children: current concepts. Curr Opin Pediatr 2019; 31:623.
  56. Harkins CP, Kong HH, Segre JA. Manipulating the Human Microbiome to Manage Disease. JAMA 2020; 323:303.
  57. Wargo JA. Modulating gut microbes. Science 2020; 369:1302.
  58. Costello SP, Hughes PA, Waters O, et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial. JAMA 2019; 321:156.
  59. Kelly CR, Ananthakrishnan AN. Manipulating the Microbiome With Fecal Transplantation to Treat Ulcerative Colitis. JAMA 2019; 321:151.
  60. Caruso R, Lo BC, Núñez G. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol 2020; 20:411.
  61. Plunkett CH, Nagler CR. The Influence of the Microbiome on Allergic Sensitization to Food. J Immunol 2017; 198:581.
  62. Wang Y, Hooper LV. Immune control of the microbiota prevents obesity. Science 2019; 365:316.
  63. Petersen C, Bell R, Klag KA, et al. T cell-mediated regulation of the microbiota protects against obesity. Science 2019; 365.
  64. Talmor-Barkan Y, Bar N, Shaul AA, et al. Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease. Nat Med 2022; 28:295.
  65. Zmora N, Soffer E, Elinav E. Transforming medicine with the microbiome. Sci Transl Med 2019; 11.
  66. Zhao L, Zhang F, Ding X, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 2018; 359:1151.
  67. Brar PC, Kohn B. Use of the microbiome in the management of children with type 2 diabetes mellitus. Curr Opin Pediatr 2019; 31:524.
  68. Pennisi E. Gut microbes may help malnourished children. Science 2019; 365:109.
  69. Gehrig JL, Venkatesh S, Chang HW, et al. Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Science 2019; 365.
  70. Chen RY, Mostafa I, Hibberd MC, et al. A Microbiota-Directed Food Intervention for Undernourished Children. N Engl J Med 2021; 384:1517.
  71. Woelk CH, Snyder A. Modulating gut microbiota to treat cancer. Science 2021; 371:573.
  72. Davar D, Dzutsev AK, McCulloch JA, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021; 371:595.
  73. Baruch EN, Youngster I, Ben-Betzalel G, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 2021; 371:602.
  74. Mirji G, Worth A, Bhat SA, et al. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci Immunol 2022; 7:eabn0704.
  75. Mackaness GB. The influence of immunologically committed lymphoid cells on macrophage activity in vivo. J Exp Med 1969; 129:973.
  76. Sasada M, Johnston RB Jr. Macrophage microbicidal activity. Correlation between phagocytosis-associated oxidative metabolism and the killing of Candida by macrophages. J Exp Med 1980; 152:85.
  77. Guthrie LA, McPhail LC, Henson PM, Johnston RB Jr. Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharide. Evidence for increased activity of the superoxide-producing enzyme. J Exp Med 1984; 160:1656.
  78. Netea MG, Domínguez-Andrés J, Barreiro LB, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol 2020; 20:375.
  79. Mantovani A, Netea MG. Trained Innate Immunity, Epigenetics, and Covid-19. N Engl J Med 2020; 383:1078.
  80. Netea MG, Quintin J, van der Meer JW. Trained immunity: a memory for innate host defense. Cell Host Microbe 2011; 9:355.
  81. Divangahi M, Aaby P, Khader SA, et al. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol 2021; 22:2.
  82. de Laval B, Maurizio J, Kandalla PK, et al. C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells. Cell Stem Cell 2020; 26:657.
  83. Mulder WJM, Ochando J, Joosten LAB, et al. Therapeutic targeting of trained immunity. Nat Rev Drug Discov 2019; 18:553.
  84. Biering-Sørensen S, Aaby P, Lund N, et al. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial. Clin Infect Dis 2017; 65:1183.
  85. Arts RJW, Moorlag SJCFM, Novakovic B, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe 2018; 23:89.
  86. Angka L, Market M, Ardolino M, Auer RC. Is innate immunity our best weapon for flattening the curve? J Clin Invest 2020; 130:3954.
  87. Covián C, Retamal-Díaz A, Bueno SM, Kalergis AM. Could BCG Vaccination Induce Protective Trained Immunity for SARS-CoV-2? Front Immunol 2020; 11:970.
  88. Escobar LE, Molina-Cruz A, Barillas-Mury C. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19). Proc Natl Acad Sci U S A 2020; 117:17720.
  89. DiNardo AR, Netea MG, Musher DM. Postinfectious Epigenetic Immune Modifications - A Double-Edged Sword. N Engl J Med 2021; 384:261.
  90. Rietschel ET, Kirikae T, Schade FU, et al. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J 1994; 8:217.
  91. Denning NL, Aziz M, Gurien SD, Wang P. DAMPs and NETs in Sepsis. Front Immunol 2019; 10:2536.
  92. Ramadan A, Land WG, Paczesny S. Editorial: Danger Signals Triggering Immune Response and Inflammation. Front Immunol 2017; 8:979.
  93. Reid KBM. Complement Component C1q: Historical Perspective of a Functionally Versatile, and Structurally Unusual, Serum Protein. Front Immunol 2018; 9:764.
  94. Cedzyński M, Thielens NM, Mollnes TE, Vorup-Jensen T. Editorial: The Role of Complement in Health and Disease. Front Immunol 2019; 10:1869.
  95. Kolev M, Kemper C. Keeping It All Going-Complement Meets Metabolism. Front Immunol 2017; 8:1.
  96. Hess C, Kemper C. Complement-Mediated Regulation of Metabolism and Basic Cellular Processes. Immunity 2016; 45:240.
  97. Park DH, Connor KM, Lambris JD. The Challenges and Promise of Complement Therapeutics for Ocular Diseases. Front Immunol 2019; 10:1007.
  98. Gavriilaki E, Brodsky RA. Complementopathies and precision medicine. J Clin Invest 2020; 130:2152.
  99. Mastellos DC, Reis ES, Lambris JD. Editorial: Therapeutic Modulation of the Complement System: Clinical Indications and Emerging Drug Leads. Front Immunol 2019; 10:3029.
  100. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature 2002; 415:389.
  101. Doss M, White MR, Tecle T, Hartshorn KL. Human defensins and LL-37 in mucosal immunity. J Leukoc Biol 2010; 87:79.
  102. Underwood MA, Bevins CL. Defensin-barbed innate immunity: clinical associations in the pediatric population. Pediatrics 2010; 125:1237.
  103. Steinstraesser L, Kraneburg U, Jacobsen F, Al-Benna S. Host defense peptides and their antimicrobial-immunomodulatory duality. Immunobiology 2011; 216:322.
  104. Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol 2010; 26:547.
  105. Tecle T, Tripathi S, Hartshorn KL. Review: Defensins and cathelicidins in lung immunity. Innate Immun 2010; 16:151.
  106. Chu H, Pazgier M, Jung G, et al. Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 2012; 337:477.
  107. Ouellette AJ, Selsted ME. Immunology. HD6 defensin nanonets. Science 2012; 337:420.
  108. Robinson MW, Hutchinson AT, Donnelly S. Antimicrobial peptides: utility players in innate immunity. Front Immunol 2012; 3:325.
  109. Campbell EL, Serhan CN, Colgan SP. Antimicrobial aspects of inflammatory resolution in the mucosa: a role for proresolving mediators. J Immunol 2011; 187:3475.
  110. Vora P, Youdim A, Thomas LS, et al. Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells. J Immunol 2004; 173:5398.
  111. Wang G, Li X, Wang Z. APD2: the updated antimicrobial peptide database and its application in peptide design. Nucleic Acids Res 2009; 37:D933.
  112. Zhang L, Wu WK, Gallo RL, et al. Critical Role of Antimicrobial Peptide Cathelicidin for Controlling Helicobacter pylori Survival and Infection. J Immunol 2016; 196:1799.
  113. Currie SM, Gwyer Findlay E, McFarlane AJ, et al. Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans. J Immunol 2016; 196:2699.
  114. Zasloff M. Antimicrobial Peptides of Multicellular Organisms: My Perspective. Adv Exp Med Biol 2019; 1117:3.
  115. Stewart BJ, Ferdinand JR, Young MD, et al. Spatiotemporal immune zonation of the human kidney. Science 2019; 365:1461.
  116. Czarnowicki T, Malajian D, Khattri S, et al. Petrolatum: Barrier repair and antimicrobial responses underlying this "inert" moisturizer. J Allergy Clin Immunol 2016; 137:1091.
  117. Wehkamp J, Stange EF. An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease. Front Immunol 2020; 11:646.
  118. Birchler T, Seibl R, Büchner K, et al. Human Toll-like receptor 2 mediates induction of the antimicrobial peptide human beta-defensin 2 in response to bacterial lipoprotein. Eur J Immunol 2001; 31:3131.
  119. Diao R, Fok KL, Chen H, et al. Deficient human β-defensin 1 underlies male infertility associated with poor sperm motility and genital tract infection. Sci Transl Med 2014; 6:249ra108.
  120. Crauwels P, Bank E, Walber B, et al. Cathelicidin Contributes to the Restriction of Leishmania in Human Host Macrophages. Front Immunol 2019; 10:2697.
  121. Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173:2909.
  122. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311:1770.
  123. Antal AS, Dombrowski Y, Koglin S, et al. Impact of vitamin D3 on cutaneous immunity and antimicrobial peptide expression. Dermatoendocrinol 2011; 3:18.
  124. Zasloff M. Fighting infections with vitamin D. Nat Med 2006; 12:388.
  125. Canny G, Levy O. Bactericidal/permeability-increasing protein (BPI) and BPI homologs at mucosal sites. Trends Immunol 2008; 29:541.
  126. Tam C, Mun JJ, Evans DJ, Fleiszig SM. Cytokeratins mediate epithelial innate defense through their antimicrobial properties. J Clin Invest 2012; 122:3665.
  127. Zasloff M. Defending the cornea with antibacterial fragments of keratin. J Clin Invest 2012; 122:3471.
  128. Paragas N, Kulkarni R, Werth M, et al. α-Intercalated cells defend the urinary system from bacterial infection. J Clin Invest 2014; 124:2963.
  129. Weiss GL, Stanisich JJ, Sauer MM, et al. Architecture and function of human uromodulin filaments in urinary tract infections. Science 2020; 369:1005.
  130. Kukulski W. A glycoprotein in urine binds bacteria and blocks infections. Science 2020; 369:917.
  131. Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science 2012; 338:768.
  132. Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest 2013; 123:2337.
  133. Núñez G, Sakamoto K, Soares MP. Innate Nutritional Immunity. J Immunol 2018; 201:11.
  134. Prchal JT. Ironing out the role of hepcidin in infection. Blood 2017; 130:233.
  135. Stefanova D, Raychev A, Arezes J, et al. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood 2017; 130:245.
  136. Bessman NJ, Mathieu JRR, Renassia C, et al. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science 2020; 368:186.
  137. Burkhardt AM, Tai KP, Flores-Guiterrez JP, et al. CXCL17 is a mucosal chemokine elevated in idiopathic pulmonary fibrosis that exhibits broad antimicrobial activity. J Immunol 2012; 188:6399.
  138. Salzman NH, Underwood MA, Bevins CL. Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin Immunol 2007; 19:70.
  139. Salzman NH, Hung K, Haribhai D, et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol 2010; 11:76.
  140. Cullen TW, Schofield WB, Barry NA, et al. Gut microbiota. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Science 2015; 347:170.
  141. Pütsep K, Carlsson G, Boman HG, Andersson M. Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet 2002; 360:1144.
  142. Ackerman DL, Craft KM, Doster RS, et al. Antimicrobial and Antibiofilm Activity of Human Milk Oligosaccharides against Streptococcus agalactiae, Staphylococcus aureus, and Acinetobacter baumannii. ACS Infect Dis 2018; 4:315.
  143. Epstein J, Eichbaum Q, Sheriff S, Ezekowitz RA. The collectins in innate immunity. Curr Opin Immunol 1996; 8:29.
  144. Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol 2005; 5:58.
  145. Wu H, Kuzmenko A, Wan S, et al. Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability. J Clin Invest 2003; 111:1589.
  146. McCormack FX, Gibbons R, Ward SR, et al. Macrophage-independent fungicidal action of the pulmonary collectins. J Biol Chem 2003; 278:36250.
  147. Lee DC, Romero R, Kim CJ, et al. Surfactant protein-A as an anti-inflammatory component in the amnion: implications for human pregnancy. J Immunol 2010; 184:6479.
  148. Fraser IP, Koziel H, Ezekowitz RA. The serum mannose-binding protein and the macrophage mannose receptor are pattern recognition molecules that link innate and adaptive immunity. Semin Immunol 1998; 10:363.
  149. Ghebrehiwet B, Hosszu KK, Valentino A, et al. Monocyte expressed macromolecular C1 and C1q receptors as molecular sensors of danger: Implications in SLE. Front Immunol 2014; 5:278.
  150. Ghebrehiwet B, Hosszu KK, Valentino A, Peerschke EI. The C1q family of proteins: insights into the emerging non-traditional functions. Front Immunol 2012; 3.
  151. Kouser L, Madhukaran SP, Shastri A, et al. Emerging and Novel Functions of Complement Protein C1q. Front Immunol 2015; 6:317.
  152. Zhou J, Hu M, Li J, et al. Mannan-Binding Lectin Regulates Inflammatory Cytokine Production, Proliferation, and Cytotoxicity of Human Peripheral Natural Killer Cells. Mediators Inflamm 2019; 2019:6738286.
  153. Hashimoto J, Takahashi M, Saito A, et al. Surfactant Protein A Inhibits Growth and Adherence of Uropathogenic Escherichia coli To Protect the Bladder from Infection. J Immunol 2017; 198:2898.
  154. Liu J, Hu F, Liang W, et al. Polymorphisms in the surfactant protein a gene are associated with the susceptibility to recurrent urinary tract infection in chinese women. Tohoku J Exp Med 2010; 221:35.
  155. Stahlman MT, Gray ME, Hull WM, Whitsett JA. Immunolocalization of surfactant protein-D (SP-D) in human fetal, newborn, and adult tissues. J Histochem Cytochem 2002; 50:651.
  156. Kishore U, Bulla R, Madan T. Editorial: Odyssey of Surfactant Proteins SP-A and SP-D: Innate Immune Surveillance Molecules. Front Immunol 2020; 11:394.
  157. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010; 11:785.
  158. Stowell SR, Arthur CM, Dias-Baruffi M, et al. Innate immune lectins kill bacteria expressing blood group antigen. Nat Med 2010; 16:295.
  159. Jack DL, Klein NJ, Turner MW. Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis. Immunol Rev 2001; 180:86.
  160. Verma A, White M, Vathipadiekal V, et al. Human H-ficolin inhibits replication of seasonal and pandemic influenza A viruses. J Immunol 2012; 189:2478.
  161. Cockram TOJ, Puigdellívol M, Brown GC. Calreticulin and Galectin-3 Opsonise Bacteria for Phagocytosis by Microglia. Front Immunol 2019; 10:2647.
  162. Świerzko AS, Cedzyński M. The Influence of the Lectin Pathway of Complement Activation on Infections of the Respiratory System. Front Immunol 2020; 11:585243.
  163. Fahy JV, Locksley RM. Making Asthma Crystal Clear. N Engl J Med 2019; 381:882.
  164. Botto M, Kirschfink M, Macor P, et al. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol 2009; 46:2774.
  165. Liu FT, Bevins CL. A sweet target for innate immunity. Nat Med 2010; 16:263.
  166. Robinson BS, Arthur CM, Evavold B, et al. The Sweet-Side of Leukocytes: Galectins as Master Regulators of Neutrophil Function. Front Immunol 2019; 10:1762.
  167. Vaishnava S, Yamamoto M, Severson KM, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 2011; 334:255.
  168. Johansson ME, Hansson GC. Microbiology. Keeping bacteria at a distance. Science 2011; 334:182.
  169. Mantovani A, Garlanda C, Doni A, Bottazzi B. Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol 2008; 28:1.
  170. Bottazzi B, Doni A, Garlanda C, Mantovani A. An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol 2010; 28:157.
  171. Deban L, Russo RC, Sironi M, et al. Regulation of leukocyte recruitment by the long pentraxin PTX3. Nat Immunol 2010; 11:328.
  172. Pepys MB. The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs. Front Immunol 2018; 9:2382.
  173. Bottazzi B, Garlanda C, Teixeira MM. Editorial: The Role of Pentraxins: From Inflammation, Tissue Repair and Immunity to Biomarkers. Front Immunol 2019; 10:2817.
  174. Haapasalo K, Meri S. Regulation of the Complement System by Pentraxins. Front Immunol 2019; 10:1750.
  175. Pathak A, Agrawal A. Evolution of C-Reactive Protein. Front Immunol 2019; 10:943.
  176. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140:805.
  177. Kumagai Y, Akira S. Identification and functions of pattern-recognition receptors. J Allergy Clin Immunol 2010; 125:985.
  178. Beutler BA. TLRs and innate immunity. Blood 2009; 113:1399.
  179. Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity 2010; 32:305.
  180. Shaw MH, Reimer T, Kim YG, Nuñez G. NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Curr Opin Immunol 2008; 20:377.
  181. Wilkins C, Gale M Jr. Recognition of viruses by cytoplasmic sensors. Curr Opin Immunol 2010; 22:41.
  182. Werner JL, Steele C. Innate receptors and cellular defense against pulmonary infections. J Immunol 2014; 193:3842.
  183. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature 2007; 449:819.
  184. Rast JP, Smith LC, Loza-Coll M, et al. Genomic insights into the immune system of the sea urchin. Science 2006; 314:952.
  185. Mukherjee S, Huda S, Sinha Babu SP. Toll-like receptor polymorphism in host immune response to infectious diseases: A review. Scand J Immunol 2019; 90:e12771.
  186. Murdock JL, Núñez G. TLR4: The Winding Road to the Discovery of the LPS Receptor. J Immunol 2016; 197:2561.
  187. Hoshino K, Takeuchi O, Kawai T, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999; 162:3749.
  188. Pabst MJ, Hedegaard HB, Johnston RB Jr. Cultured human monocytes require exposure to bacterial products to maintain an optimal oxygen radical response. J Immunol 1982; 128:123.
  189. Stein MM, Hrusch CL, Gozdz J, et al. Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. N Engl J Med 2016; 375:411.
  190. Chatila TA. Innate Immunity in Asthma. N Engl J Med 2016; 375:477.
  191. Gay NJ, Keith FJ. Drosophila Toll and IL-1 receptor. Nature 1991; 351:355.
  192. Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science 2007; 317:1522.
  193. Casrouge A, Zhang SY, Eidenschenk C, et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 2006; 314:308.
  194. Dupuis S, Jouanguy E, Al-Hajjar S, et al. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 2003; 33:388.
  195. Zhang SY, Jouanguy E, Sancho-Shimizu V, et al. Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunol Rev 2007; 220:225.
  196. Crispe IN. Hepatocytes as Immunological Agents. J Immunol 2016; 196:17.
  197. Tulic MK, Hurrelbrink RJ, Prêle CM, et al. TLR4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide. J Immunol 2007; 179:132.
  198. Pamer EG. TLR polymorphisms and the risk of invasive fungal infections. N Engl J Med 2008; 359:1836.
  199. Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol 2012; 188:818.
  200. Urban-Wojciuk Z, Khan MM, Oyler BL, et al. The Role of TLRs in Anti-cancer Immunity and Tumor Rejection. Front Immunol 2019; 10:2388.
  201. Egesten A, Schmidt A, Herwald H. Trends in innate immunity.. In: Contributions to microbiology, Karger, Basel 2008. Vol 15, p.14.
  202. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 2007; 117:1175.
  203. Netea MG, Gow NA, Munro CA, et al. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 2006; 116:1642.
  204. Thomas CA, Li Y, Kodama T, et al. Protection from lethal gram-positive infection by macrophage scavenger receptor-dependent phagocytosis. J Exp Med 2000; 191:147.
  205. Fabriek BO, van Bruggen R, Deng DM, et al. The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria. Blood 2009; 113:887.
  206. Thelen T, Hao Y, Medeiros AI, et al. The class A scavenger receptor, macrophage receptor with collagenous structure, is the major phagocytic receptor for Clostridium sordellii expressed by human decidual macrophages. J Immunol 2010; 185:4328.
  207. Willment JA, Marshall AS, Reid DM, et al. The human beta-glucan receptor is widely expressed and functionally equivalent to murine Dectin-1 on primary cells. Eur J Immunol 2005; 35:1539.
  208. Levitz SM. Innate recognition of fungal cell walls. PLoS Pathog 2010; 6:e1000758.
  209. Marakalala MJ, Kerrigan AM, Brown GD. Dectin-1: a role in antifungal defense and consequences of genetic polymorphisms in humans. Mamm Genome 2011; 22:55.
  210. Ferwerda B, Ferwerda G, Plantinga TS, et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med 2009; 361:1760.
  211. Glocker EO, Hennigs A, Nabavi M, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 2009; 361:1727.
  212. Le Y, Yang Y, Cui Y, et al. Receptors for chemotactic formyl peptides as pharmacological targets. Int Immunopharmacol 2002; 2:1.
  213. Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140:821.
  214. Lamkanfi M, Dixit VM. In Retrospect: The inflammasome turns 15. Nature 2017; 548:534.
  215. Yang Y, Wang H, Kouadir M, et al. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis 2019; 10:128.
  216. Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int J Mol Sci 2019; 20.
  217. Inohara N, Nuñez G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 2003; 3:371.
  218. Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem 2003; 278:5509.
  219. Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003; 278:8869.
  220. Rosenstiel P, Fantini M, Bräutigam K, et al. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology 2003; 124:1001.
  221. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009; 361:2066.
  222. Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol 2004; 99:2393.
  223. Sidiq T, Yoshihama S, Downs I, Kobayashi KS. Nod2: A Critical Regulator of Ileal Microbiota and Crohn's Disease. Front Immunol 2016; 7:367.
  224. Kato H, Takeuchi O, Sato S, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006; 441:101.
  225. Netea MG, van de Veerdonk FL, van der Meer JW. Primary immunodeficiencies of pattern recognition receptors. J Intern Med 2012; 272:517.
  226. Johnston RB Jr, Babior BM. The polymorphonuclear leukocyte system. In: Immunologic disorders in infants and children, 5th ed, Stiehm ER, Ochs HD, Winkelstein JA (Eds), Saunders/Elsevier, Philadelphia 2004. p.109.
  227. Silva MT. When two is better than one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system. J Leukoc Biol 2010; 87:93.
  228. Serbina NV, Jia T, Hohl TM, Pamer EG. Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 2008; 26:421.
  229. Rossi M, Young JW. Human dendritic cells: potent antigen-presenting cells at the crossroads of innate and adaptive immunity. J Immunol 2005; 175:1373.
  230. Liu K, Nussenzweig MC. Origin and development of dendritic cells. Immunol Rev 2010; 234:45.
  231. Berliner N, Coates TD. Introduction to a review series on human neutrophils. Blood 2019; 133:2111.
  232. Rehaume LM, Hancock RE. Neutrophil-derived defensins as modulators of innate immune function. Crit Rev Immunol 2008; 28:185.
  233. Matlung HL, Babes L, Zhao XW, et al. Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis. Cell Rep 2018; 23:3946.
  234. Nauseef WM. How human neutrophils kill and degrade microbes: an integrated view. Immunol Rev 2007; 219:88.
  235. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000; 79:155.
  236. Reeves EP, Lu H, Jacobs HL, et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 2002; 416:291.
  237. Papayannopoulos V. Actin powers the neutrophil traps. Blood 2022; 139:3104.
  238. Sprenkeler EGG, Tool ATJ, Henriet SSV, et al. Formation of neutrophil extracellular traps requires actin cytoskeleton rearrangements. Blood 2022; 139:3166.
  239. Yipp BG, Petri B, Salina D, et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012; 18:1386.
  240. Peschel A, Hartl D. Anuclear neutrophils keep hunting. Nat Med 2012; 18:1336.
  241. Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol 2012; 189:2689.
  242. Schauer C, Janko C, Munoz LE, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med 2014; 20:511.
  243. Ramirez GA, Manfredi AA, Rovere-Querini P, Maugeri N. Bet on NETs! Or on How to Translate Basic Science into Clinical Practice. Front Immunol 2016; 7:417.
  244. Mohanty T, Sjögren J, Kahn F, et al. A novel mechanism for NETosis provides antimicrobial defense at the oral mucosa. Blood 2015; 126:2128.
  245. Hartl D. Oral NETs: the deadly kiss. Blood 2015; 126:2079.
  246. Branzk N, Lubojemska A, Hardison SE, et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol 2014; 15:1017.
  247. Noubouossie DF, Reeves BN, Strahl BD, Key NS. Neutrophils: back in the thrombosis spotlight. Blood 2019; 133:2186.
  248. Franchi T, Eaton S, De Coppi P, Giuliani S. The emerging role of immunothrombosis in paediatric conditions. Pediatr Res 2019; 86:19.
  249. Fábián TK, Hermann P, Beck A, et al. Salivary defense proteins: their network and role in innate and acquired oral immunity. Int J Mol Sci 2012; 13:4295.
  250. Chiang N, Sakuma M, Rodriguez AR, et al. Resolvin T-series reduce neutrophil extracellular traps. Blood 2022; 139:1222.
  251. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 2015; 349:316.
  252. Yipp BG, Kubes P. NETosis: how vital is it? Blood 2013; 122:2784.
  253. Saffarzadeh M, Preissner KT. Fighting against the dark side of neutrophil extracellular traps in disease: manoeuvres for host protection. Curr Opin Hematol 2013; 20:3.
  254. Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med 2017; 23:279.
  255. Corsiero E, Pratesi F, Prediletto E, et al. NETosis as Source of Autoantigens in Rheumatoid Arthritis. Front Immunol 2016; 7:485.
  256. Pietronigro EC, Della Bianca V, Zenaro E, Constantin G. NETosis in Alzheimer's Disease. Front Immunol 2017; 8:211.
  257. Lefrançais E, Mallavia B, Zhuo H, et al. Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. JCI Insight 2018; 3.
  258. Toussaint M, Jackson DJ, Swieboda D, et al. Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation. Nat Med 2017; 23:681.
  259. Hartl D. Macrophages and platelets join forces to release kidney-damaging DNA traps. Nat Med 2018; 24:128.
  260. Castanheira FVS, Kubes P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood 2019; 133:2178.
  261. Granger V, Peyneau M, Chollet-Martin S, de Chaisemartin L. Neutrophil Extracellular Traps in Autoimmunity and Allergy: Immune Complexes at Work. Front Immunol 2019; 10:2824.
  262. Ghebrehiwet B, Peerschke EI. Complement and coagulation: key triggers of COVID-19-induced multiorgan pathology. J Clin Invest 2020; 130:5674.
  263. Skendros P, Mitsios A, Chrysanthopoulou A, et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J Clin Invest 2020; 130:6151.
  264. Margraf A, Lowell CA, Zarbock A. Neutrophils in acute inflammation: current concepts and translational implications. Blood 2022; 139:2130.
  265. Surolia R, Li FJ, Wang Z, et al. NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns. JCI Insight 2021; 6.
  266. Parisien M, Lima LV, Dagostino C, et al. Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med 2022; 14:eabj9954.
  267. Leslie M. The body's dangerous defenders. Science 2020; 367:1067.
  268. Jiménez-Alcázar M, Rangaswamy C, Panda R, et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 2017; 358:1202.
  269. Gunzer M. Escaping the traps of your own hunters. Science 2017; 358:1126.
  270. Silvestre-Roig C, Hidalgo A, Soehnlein O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood 2016; 127:2173.
  271. Rocha-Gregg BL, Huttenlocher A. Swarming motility in host defense. Science 2021; 372:1262.
  272. Kienle K, Glaser KM, Eickhoff S, et al. Neutrophils self-limit swarming to contain bacterial growth in vivo. Science 2021; 372.
  273. Coillard A, Segura E. In vivo Differentiation of Human Monocytes. Front Immunol 2019; 10:1907.
  274. Jakubzick C, Gautier EL, Gibbings SL, et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 2013; 39:599.
  275. Nicolás-Ávila JA, Lechuga-Vieco AV, Esteban-Martínez L, et al. A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart. Cell 2020; 183:94.
  276. McNally EM. Cardiac Macrophages - Keeping the Engine Running Clean. N Engl J Med 2020; 383:2474.
  277. Sieweke MH, Allen JE. Beyond stem cells: self-renewal of differentiated macrophages. Science 2013; 342:1242974.
  278. Yona S, Kim KW, Wolf Y, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 2013; 38:79.
  279. Katsumoto A, Lu H, Miranda AS, Ransohoff RM. Ontogeny and functions of central nervous system macrophages. J Immunol 2014; 193:2615.
  280. Mass E, Ballesteros I, Farlik M, et al. Specification of tissue-resident macrophages during organogenesis. Science 2016; 353.
  281. Villani AC, Satija R, Reynolds G, et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 2017; 356.
  282. Svedberg FR, Guilliams M. Cellular origin of human cardiac macrophage populations. Nat Med 2018; 24:1091.
  283. Gordon S, Plüddemann A. The Mononuclear Phagocytic System. Generation of Diversity. Front Immunol 2019; 10:1893.
  284. Dey A, Allen J, Hankey-Giblin PA. Ontogeny and polarization of macrophages in inflammation: blood monocytes versus tissue macrophages. Front Immunol 2014; 5:683.
  285. Mills CD, Lenz LL, Ley K. Macrophages at the fork in the road to health or disease. Front Immunol 2015; 6:59.
  286. Gomez Perdiguero E, Geissmann F. Cancer immunology. Identifying the infiltrators. Science 2014; 344:801.
  287. Franklin RA, Liao W, Sarkar A, et al. The cellular and molecular origin of tumor-associated macrophages. Science 2014; 344:921.
  288. Gomez Perdiguero E, Klapproth K, Schulz C, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 2015; 518:547.
  289. Parks BW, Lusis AJ. Macrophage accumulation in atherosclerosis. N Engl J Med 2013; 369:2352.
  290. Tabas I, Lichtman AH. Monocyte-Macrophages and T Cells in Atherosclerosis. Immunity 2017; 47:621.
  291. Ley K. M1 Means Kill; M2 Means Heal. J Immunol 2017; 199:2191.
  292. Richter FC, Udalova I. Macrophage commonalities across tissues and inflammation. Nat Rev Immunol 2022; 22:2.
  293. Nguyen RH, Kubes P. Bespoke brain immunity. Science 2021; 373:396.
  294. Cugurra A, Mamuladze T, Rustenhoven J, et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science 2021; 373.
  295. Kwon D. Guardians of the brain: how a special immune system protects our grey matter. Nature 2022; 606:22.
  296. Schlesinger L, Musson RA, Johnston RB Jr. Functional and biochemical studies of multinucleated giant cells derived from the culture of human monocytes. J Exp Med 1984; 159:1289.
  297. Milde R, Ritter J, Tennent GA, et al. Multinucleated Giant Cells Are Specialized for Complement-Mediated Phagocytosis and Large Target Destruction. Cell Rep 2015; 13:1937.
  298. Winn NC, Volk KM, Hasty AH. Regulation of tissue iron homeostasis: the macrophage "ferrostat". JCI Insight 2020; 5.
  299. Mezu-Ndubuisi OJ, Maheshwari A. Role of macrophages in fetal development and perinatal disorders. Pediatr Res 2021; 90:513.
  300. Kawamura Y, Mogami H, Yasuda E, et al. Fetal macrophages assist in the repair of ruptured amnion through the induction of epithelial-mesenchymal transition. Sci Signal 2022; 15:eabi5453.
  301. Kierdorf K, Prinz M. Microglia in steady state. J Clin Invest 2017; 127:3201.
  302. Lenz KM, Nelson LH. Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function. Front Immunol 2018; 9:698.
  303. Tambuyzer BR, Ponsaerts P, Nouwen EJ. Microglia: gatekeepers of central nervous system immunology. J Leukoc Biol 2009; 85:352.
  304. Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology 2010; 129:154.
  305. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest 2012; 122:1164.
  306. Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science 2016; 353:777.
  307. Klein RS, Hunter CA. Protective and Pathological Immunity during Central Nervous System Infections. Immunity 2017; 46:891.
  308. Priller J, Prinz M. Targeting microglia in brain disorders. Science 2019; 365:32.
  309. Slomski A. Air Quality and Brain Health. JAMA 2022; 327:1430.
  310. Ueki S, Melo RC, Ghiran I, et al. Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans. Blood 2013; 121:2074.
  311. Marx C, Novotny J, Salbeck D, et al. Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps. Blood 2019; 134:1859.
  312. Jung Y, Rothenberg ME. Roles and regulation of gastrointestinal eosinophils in immunity and disease. J Immunol 2014; 193:999.
  313. Baehner RL, Johnston RB Jr. Metabolic and bactericidal activities of human eosinophils. Br J Haematol 1971; 20:277.
  314. Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol 2004; 113:11.
  315. Oyoshi MK. Recent research advances in eosinophilic esophagitis. Curr Opin Pediatr 2015; 27:741.
  316. Furuta GT, Katzka DA. Eosinophilic Esophagitis. N Engl J Med 2015; 373:1640.
  317. Akuthota P, Neves JS, Ueki S. Editorial: Severe Eosinophilic Disorders: Mechanisms and Clinical Management. Front Immunol 2019; 10:2118.
  318. Doyle AD, Masuda MY, Kita H, Wright BL. Eosinophils in Eosinophilic Esophagitis: The Road to Fibrostenosis is Paved With Good Intentions. Front Immunol 2020; 11:603295.
  319. Muir A, Falk GW. Eosinophilic Esophagitis: A Review. JAMA 2021; 326:1310.
  320. Lu Y, Huang Y, Li J, et al. Eosinophil extracellular traps drive asthma progression through neuro-immune signals. Nat Cell Biol 2021; 23:1060.
  321. Dudeck J, Kotrba J, Immler R, et al. Directional mast cell degranulation of tumor necrosis factor into blood vessels primes neutrophil extravasation. Immunity 2021; 54:468.
  322. Varadaradjalou S, Féger F, Thieblemont N, et al. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. Eur J Immunol 2003; 33:899.
  323. Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol 2010; 10:440.
  324. Shelburne CP, Abraham SN. The mast cell in innate and adaptive immunity. Adv Exp Med Biol 2011; 716:162.
  325. Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med 2015; 373:163.
  326. St John AL, Abraham SN. Innate immunity and its regulation by mast cells. J Immunol 2013; 190:4458.
  327. Lu F, Huang S. The Roles of Mast Cells in Parasitic Protozoan Infections. Front Immunol 2017; 8:363.
  328. De Zuani M, Paolicelli G, Zelante T, et al. Mast Cells Respond to Candida albicans Infections and Modulate Macrophages Phagocytosis of the Fungus. Front Immunol 2018; 9:2829.
  329. Ragipoglu D, Dudeck A, Haffner-Luntzer M, et al. The Role of Mast Cells in Bone Metabolism and Bone Disorders. Front Immunol 2020; 11:163.
  330. Park MD, Merad M. Cooperation between the alveolar epithelium and lung-resident basophils shapes alveolar macrophages. Nat Rev Immunol 2021; 21:344.
  331. Mukai K, Tsai M, Saito H, Galli SJ. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev 2018; 282:121.
  332. Steiner M, Huber S, Harrer A, Himly M. The Evolution of Human Basophil Biology from Neglect towards Understanding of Their Immune Functions. Biomed Res Int 2016; 2016:8232830.
  333. Olivera A, Laky K, Hogan SP, Frischmeyer-Guerrerio P. Editorial: Innate Cells in the Pathogenesis of Food Allergy. Front Immunol 2021; 12:709991.
  334. Paust S, Senman B, von Andrian UH. Adaptive immune responses mediated by natural killer cells. Immunol Rev 2010; 235:286.
  335. Cooper MA, Yokoyama WM. Memory-like responses of natural killer cells. Immunol Rev 2010; 235:297.
  336. Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science 2011; 331:44.
  337. Sun JC, Lopez-Verges S, Kim CC, et al. NK cells and immune "memory". J Immunol 2011; 186:1891.
  338. Paust S, von Andrian UH. Natural killer cell memory. Nat Immunol 2011; 12:500.
  339. Marcenaro E, Notarangelo LD, Orange JS, Vivier E. Editorial: NK Cell Subsets in Health and Disease: New Developments. Front Immunol 2017; 8:1363.
  340. Nikzad R, Angelo LS, Aviles-Padilla K, et al. Human natural killer cells mediate adaptive immunity to viral antigens. Sci Immunol 2019; 4.
  341. Björkström NK, Strunz B, Ljunggren HG. Natural killer cells in antiviral immunity. Nat Rev Immunol 2022; 22:112.
  342. Lauzon NM, Mian F, MacKenzie R, Ashkar AA. The direct effects of Toll-like receptor ligands on human NK cell cytokine production and cytotoxicity. Cell Immunol 2006; 241:102.
  343. Hart OM, Athie-Morales V, O'Connor GM, Gardiner CM. TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol 2005; 175:1636.
  344. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2:735.
  345. Wagtmann N, Rajagopalan S, Winter CC, et al. Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer. Immunity 1995; 3:801.
  346. Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol 2001; 1:41.
  347. Mysorekar IU. Killing the Pathogen and Sparing the Placenta. N Engl J Med 2020; 383:2080.
  348. Rouse BT, Sehrawat S. Immunity and immunopathology to viruses: what decides the outcome? Nat Rev Immunol 2010; 10:514.
  349. Biron CA, Byron KS, Sullivan JL. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 1989; 320:1731.
  350. Tobin LM, Mavinkurve M, Carolan E, et al. NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight 2017; 2.
  351. Sellami M, Gasmi M, Denham J, et al. Effects of Acute and Chronic Exercise on Immunological Parameters in the Elderly Aged: Can Physical Activity Counteract the Effects of Aging? Front Immunol 2018; 9:2187.
  352. Fehervari Z. Young versus old. Nat Immunol 2022; 23:150.
  353. Meffre E, Iwasaki A. Interferon deficiency can lead to severe COVID. Nature 2020; 587:374.
  354. Beck DB, Aksentijevich I. Susceptibility to severe COVID-19. Science 2020; 370:404.
  355. Zhang Q, Bastard P, Liu Z, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020; 370.
  356. Bastard P, Rosen LB, Zhang Q, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020; 370.
  357. Eberl G, Colonna M, Di Santo JP, McKenzie AN. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science 2015; 348:aaa6566.
  358. Walker JA, Barlow JL, McKenzie AN. Innate lymphoid cells--how did we miss them? Nat Rev Immunol 2013; 13:75.
  359. Rosenbaum JT. The Immune Response--Learning to Leave Well Enough Alone. N Engl J Med 2015; 373:2378.
  360. Hepworth MR, Fung TC, Masur SH, et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4⁺ T cells. Science 2015; 348:1031.
  361. Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med 2015; 21:698.
  362. Panda SK, Colonna M. Innate Lymphoid Cells in Mucosal Immunity. Front Immunol 2019; 10:861.
  363. Cobb LM, Verneris MR. Therapeutic manipulation of innate lymphoid cells. JCI Insight 2021; 6.
  364. Withers DR, Hepworth MR. Group 3 Innate Lymphoid Cells: Communications Hubs of the Intestinal Immune System. Front Immunol 2017; 8:1298.
  365. Nixon BG, Li MO. Tissue-Resident Cytolytic Innate Lymphocytes in Cancer. J Immunol 2018; 200:408.
  366. Ercolano G, Falquet M, Vanoni G, et al. ILC2s: New Actors in Tumor Immunity. Front Immunol 2019; 10:2801.
  367. Hepworth MR, Monticelli LA, Fung TC, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 2013; 498:113.
  368. Nussbaum JC, Van Dyken SJ, von Moltke J, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 2013; 502:245.
  369. Goto Y, Obata T, Kunisawa J, et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 2014; 345:1254009.
  370. Geremia A, Arancibia-Cárcamo CV. Innate Lymphoid Cells in Intestinal Inflammation. Front Immunol 2017; 8:1296.
  371. Clark R, Kupper T. Old meets new: the interaction between innate and adaptive immunity. J Invest Dermatol 2005; 125:629.
  372. Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 2006; 311:17.
  373. Steinman RM. Lasker Basic Medical Research Award. Dendritic cells: versatile controllers of the immune system. Nat Med 2007; 13:1155.
  374. Liu K, Victora GD, Schwickert TA, et al. In vivo analysis of dendritic cell development and homeostasis. Science 2009; 324:392.
  375. van Spriel AB, de Jong EC. Dendritic cell science: more than 40 years of history. J Leukoc Biol 2013; 93:33.
  376. Longhi MP, Trumpfheller C, Idoyaga J, et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med 2009; 206:1589.
  377. Kaplan JL, Shi HN, Walker WA. The role of microbes in developmental immunologic programming. Pediatr Res 2011; 69:465.
  378. Jiménez-Baranda S, Silva IP, Bhardwaj N. Plasmacytoid dendritic cells lead the charge against tumors. J Clin Invest 2012; 122:481.
  379. Chan JK, Roth J, Oppenheim JJ, et al. Alarmins: awaiting a clinical response. J Clin Invest 2012; 122:2711.
  380. Jarrossay D, Napolitani G, Colonna M, et al. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001; 31:3388.
  381. Hayes MP, Wang J, Norcross MA. Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-gamma of lipopolysaccharide-inducible p35 and p40 genes. Blood 1995; 86:646.
  382. Ma X, Chow JM, Gri G, et al. The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med 1996; 183:147.
  383. Nathan C. Rethinking immunology. Science 2021; 373:276.
  384. Nakanaga T, Nadel JA, Ueki IF, et al. Regulation of interleukin-8 via an airway epithelial signaling cascade. Am J Physiol Lung Cell Mol Physiol 2007; 292:L1289.
  385. Amatngalim GD, van Wijck Y, de Mooij-Eijk Y, et al. Basal cells contribute to innate immunity of the airway epithelium through production of the antimicrobial protein RNase 7. J Immunol 2015; 194:3340.
  386. Szolnoky G, Bata-Csörgö Z, Kenderessy AS, et al. A mannose-binding receptor is expressed on human keratinocytes and mediates killing of Candida albicans. J Invest Dermatol 2001; 117:205.
  387. Miller LS, Cho JS. Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol 2011; 11:505.
  388. Bel S, Pendse M, Wang Y, et al. Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Science 2017; 357:1047.
  389. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004; 118:229.
  390. Gillaux C, Méhats C, Vaiman D, et al. Functional screening of TLRs in human amniotic epithelial cells. J Immunol 2011; 187:2766.
  391. Nyström EEL, Martinez-Abad B, Arike L, et al. An intercrypt subpopulation of goblet cells is essential for colonic mucus barrier function. Science 2021; 372.
  392. Lee RJ, Kofonow JM, Rosen PL, et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J Clin Invest 2014; 124:1393.
  393. Howitt MR, Lavoie S, Michaud M, et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 2016; 351:1329.
  394. Leslie M. Taste for danger. Science 2019; 363:1378.
  395. Boilard E, Flamand L. The role of the megakaryocyte in immunity has gone viral. Blood 2019; 133:2001.
  396. Campbell RA, Schwertz H, Hottz ED, et al. Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3. Blood 2019; 133:2013.
  397. Semple JW, Freedman J. Platelets and innate immunity. Cell Mol Life Sci 2010; 67:499.
  398. Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science 2010; 328:562.
  399. McMorran BJ, Wieczorski L, Drysdale KE, et al. Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. Science 2012; 338:1348.
  400. Engwerda CR, Good MF. Immunology. Platelets kill the parasite within. Science 2012; 338:1304.
  401. Rondina MT, Garraud O. Emerging evidence for platelets as immune and inflammatory effector cells. Front Immunol 2014; 5:653.
  402. Kapur R, Zufferey A, Boilard E, Semple JW. Nouvelle cuisine: platelets served with inflammation. J Immunol 2015; 194:5579.
  403. Rossaint J, Margraf A, Zarbock A. Role of Platelets in Leukocyte Recruitment and Resolution of Inflammation. Front Immunol 2018; 9:2712.
  404. Guo L, Rondina MT. The Era of Thromboinflammation: Platelets Are Dynamic Sensors and Effector Cells During Infectious Diseases. Front Immunol 2019; 10:2204.
  405. McDonald B, Dunbar M. Platelets and Intravascular Immunity: Guardians of the Vascular Space During Bloodstream Infections and Sepsis. Front Immunol 2019; 10:2400.
  406. Sreeramkumar V, Adrover JM, Ballesteros I, et al. Neutrophils scan for activated platelets to initiate inflammation. Science 2014; 346:1234.
  407. Ali RA, Wuescher LM, Dona KR, Worth RG. Platelets Mediate Host Defense against Staphylococcus aureus through Direct Bactericidal Activity and by Enhancing Macrophage Activities. J Immunol 2017; 198:344.
  408. Burnouf T, Walker TL. The multifaceted role of platelets in mediating brain function. Blood 2022; 140:815.
  409. Morrell CN, Aggrey AA, Chapman LM, Modjeski KL. Emerging roles for platelets as immune and inflammatory cells. Blood 2014; 123:2759.
  410. Garraud O. Editorial: Platelets as Immune Cells in Physiology and Immunopathology. Front Immunol 2015; 6:274.
  411. Anderson HL, Brodsky IE, Mangalmurti NS. The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity. J Immunol 2018; 201:1343.
  412. Leslie M. Red blood cells may be immune sentinels. Science 2021; 374:383.
  413. Lam LKM, Murphy S, Kokkinaki D, et al. DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia. Sci Transl Med 2021; 13:eabj1008.
  414. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007; 117:289.
  415. Chavan SS, Tracey KJ. Essential Neuroscience in Immunology. J Immunol 2017; 198:3389.
  416. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853.
  417. Weidinger C, Ziegler JF, Letizia M, et al. Adipokines and Their Role in Intestinal Inflammation. Front Immunol 2018; 9:1974.
  418. Cypess AM. Reassessing Human Adipose Tissue. N Engl J Med 2022; 386:768.
  419. Ferrante AW Jr. Macrophages, fat, and the emergence of immunometabolism. J Clin Invest 2013; 123:4992.
  420. Han JM, Levings MK. Immune regulation in obesity-associated adipose inflammation. J Immunol 2013; 191:527.
  421. Carvalheira JB, Qiu Y, Chawla A. Blood spotlight on leukocytes and obesity. Blood 2013; 122:3263.
  422. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 2012; 18:363.
  423. McLaughlin T, Ackerman SE, Shen L, Engleman E. Role of innate and adaptive immunity in obesity-associated metabolic disease. J Clin Invest 2017; 127:5.
  424. Blaszczak AM, Jalilvand A, Hsueh WA. Adipocytes, Innate Immunity and Obesity: A Mini-Review. Front Immunol 2021; 12:650768.
  425. Zhang LJ, Guerrero-Juarez CF, Hata T, et al. Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 2015; 347:67.
  426. Holt PG, Oliver J, Bilyk N, et al. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. J Exp Med 1993; 177:397.
  427. Lambrecht BN. Alveolar macrophage in the driver's seat. Immunity 2006; 24:366.
  428. Takabayshi K, Corr M, Hayashi T, et al. Induction of a homeostatic circuit in lung tissue by microbial compounds. Immunity 2006; 24:475.
  429. Nicolás-Ávila JÁ, Adrover JM, Hidalgo A. Neutrophils in Homeostasis, Immunity, and Cancer. Immunity 2017; 46:15.
  430. Christoffersson G, Vågesjö E, Vandooren J, et al. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood 2012; 120:4653.
  431. Kolaczkowska E, Kubes P. Phagocytes & granulocytes. Angiogenic neutrophils: a novel subpopulation paradigm. Blood 2012; 120:4455.
  432. Pillay J, Kamp VM, van Hoffen E, et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest 2012; 122:327.
  433. Jacobsen EA, Helmers RA, Lee JJ, Lee NA. The expanding role(s) of eosinophils in health and disease. Blood 2012; 120:3882.
  434. Mesnil C, Raulier S, Paulissen G, et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J Clin Invest 2016; 126:3279.
  435. Sulciner ML, Serhan CN, Gilligan MM, et al. Resolvins suppress tumor growth and enhance cancer therapy. J Exp Med 2018; 215:115.
  436. Godson C. Balancing the Effect of Leukotrienes in Asthma. N Engl J Med 2020; 382:1472.
  437. Lee CR, Zeldin DC. Resolvin Infectious Inflammation by Targeting the Host Response. N Engl J Med 2015; 373:2183.
  438. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature 2014; 510:92.
  439. Ungaro F, Rubbino F, Danese S, D'Alessio S. Actors and Factors in the Resolution of Intestinal Inflammation: Lipid Mediators As a New Approach to Therapy in Inflammatory Bowel Diseases. Front Immunol 2017; 8:1331.
  440. Dalli J, Serhan CN. Pro-Resolving Mediators in Regulating and Conferring Macrophage Function. Front Immunol 2017; 8:1400.
  441. Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest 2018; 128:2657.
  442. Conte MS, Desai TA, Wu B, et al. Pro-resolving lipid mediators in vascular disease. J Clin Invest 2018; 128:3727.
  443. Dalli J, Chiang N, Serhan CN. Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat Med 2015; 21:1071.
  444. Orkaby AR, Driver JA, Ho YL, et al. Association of Statin Use With All-Cause and Cardiovascular Mortality in US Veterans 75 Years and Older. JAMA 2020; 324:68.
  445. Bisgaard H, Stokholm J, Chawes BL, et al. Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring. N Engl J Med 2016; 375:2530.
  446. Ramsden CE. Breathing Easier with Fish Oil - A New Approach to Preventing Asthma? N Engl J Med 2016; 375:2596.
  447. Levy BD, Serhan CN. Resolution of acute inflammation in the lung. Annu Rev Physiol 2014; 76:467.
  448. Ramaswami R, Serhan CN, Levy BD, Makrides M. Fish Oil Supplementation in Pregnancy. N Engl J Med 2016; 375:2599.
  449. Vandivier RW, Henson PM, Douglas IS. Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 2006; 129:1673.
  450. Henson PM, Bratton DL. Antiinflammatory effects of apoptotic cells. J Clin Invest 2013; 123:2773.
  451. Kourtzelis I, Hajishengallis G, Chavakis T. Phagocytosis of Apoptotic Cells in Resolution of Inflammation. Front Immunol 2020; 11:553.
  452. Walker RI, Willemze R. Neutrophil kinetics and the regulation of granulopoiesis. Rev Infect Dis 1980; 2:282.
  453. Akbar AN, Gilroy DW. Aging immunity may exacerbate COVID-19. Science 2020; 369:256.
  454. De Maeyer RPH, van de Merwe RC, Louie R, et al. Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat Immunol 2020; 21:615.
  455. Newton K, Dixit VM, Kayagaki N. Dying cells fan the flames of inflammation. Science 2021; 374:1076.
  456. Fox S, Leitch AE, Duffin R, et al. Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease. J Innate Immun 2010; 2:216.
  457. Devitt A, Marshall LJ. The innate immune system and the clearance of apoptotic cells. J Leukoc Biol 2011; 90:447.
  458. Elliott MR, Koster KM, Murphy PS. Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses. J Immunol 2017; 198:1387.
  459. Han CZ, Juncadella IJ, Kinchen JM, et al. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature 2016; 539:570.
  460. Trahtemberg U, Mevorach D. Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells. Front Immunol 2017; 8:1356.
  461. Henson PM. Cell Removal: Efferocytosis. Annu Rev Cell Dev Biol 2017; 33:127.
  462. Gordon S, Plüddemann A. Macrophage Clearance of Apoptotic Cells: A Critical Assessment. Front Immunol 2018; 9:127.
  463. Fadok VA, Voelker DR, Campbell PA, et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992; 148:2207.
  464. Fadok VA, Bratton DL, Rose DM, et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 2000; 405:85.
  465. Fadeel B, Xue D, Kagan V. Programmed cell clearance: molecular regulation of the elimination of apoptotic cell corpses and its role in the resolution of inflammation. Biochem Biophys Res Commun 2010; 396:7.
  466. Parihar A, Eubank TD, Doseff AI. Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death. J Innate Immun 2010; 2:204.
  467. Silva MT. Bacteria-induced phagocyte secondary necrosis as a pathogenicity mechanism. J Leukoc Biol 2010; 88:885.
  468. Banerjee S, Friggeri A, Liu G, Abraham E. The C-terminal acidic tail is responsible for the inhibitory effects of HMGB1 on efferocytosis. J Leukoc Biol 2010; 88:973.
  469. Devaraj A, Novotny LA, Robledo-Avila FH, et al. The extracellular innate-immune effector HMGB1 limits pathogenic bacterial biofilm proliferation. J Clin Invest 2021; 131.
  470. Westman J, Grinstein S, Marques PE. Phagocytosis of Necrotic Debris at Sites of Injury and Inflammation. Front Immunol 2019; 10:3030.
  471. Vandivier RW, Ogden CA, Fadok VA, et al. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J Immunol 2002; 169:3978.
  472. Galvan MD, Greenlee-Wacker MC, Bohlson SS. C1q and phagocytosis: the perfect complement to a good meal. J Leukoc Biol 2012; 92:489.
  473. Muñoz LE, Lauber K, Schiller M, et al. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol 2010; 6:280.
  474. Johnston RB Jr. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol 2001; 8:17.
  475. Ligeti E, Geiszt M. CGD: less is more. Blood 2020; 135:883.
  476. Segal BH, Han W, Bushey JJ, et al. NADPH oxidase limits innate immune responses in the lungs in mice. PLoS One 2010; 5:e9631.
  477. Fernandez-Boyanapalli RF, Frasch SC, McPhillips K, et al. Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4. Blood 2009; 113:2047.
  478. Fernandez-Boyanapalli R, McPhillips KA, Frasch SC, et al. Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner. J Immunol 2010; 185:4030.
  479. Hou B, Saudan P, Ott G, et al. Selective utilization of Toll-like receptor and MyD88 signaling in B cells for enhancement of the antiviral germinal center response. Immunity 2011; 34:375.
  480. Black M, Trent A, Tirrell M, Olive C. Advances in the design and delivery of peptide subunit vaccines with a focus on toll-like receptor agonists. Expert Rev Vaccines 2010; 9:157.
  481. Zhu Q, Egelston C, Vivekanandhan A, et al. Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc Natl Acad Sci U S A 2008; 105:16260.
  482. Blander JM, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 2006; 440:808.
  483. DRESSER DW. Effectiveness of lipid and lipidophilic substances as adjuvants. Nature 1961; 191:1169.
  484. Vella AT, McCormack JE, Linsley PS, et al. Lipopolysaccharide interferes with the induction of peripheral T cell death. Immunity 1995; 2:261.
  485. Pape KA, Khoruts A, Mondino A, Jenkins MK. Inflammatory cytokines enhance the in vivo clonal expansion and differentiation of antigen-activated CD4+ T cells. J Immunol 1997; 159:591.
  486. Wood JH, Partrick DA, Johnston RB Jr. The inflammatory response to injury in children. Curr Opin Pediatr 2010; 22:315.
  487. Aziz M, Jacob A, Yang WL, et al. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol 2013; 93:329.
  488. Muszynski JA, Thakkar R, Hall MW. Inflammation and innate immune function in critical illness. Curr Opin Pediatr 2016; 28:267.
  489. Hall MW, Knatz NL, Vetterly C, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med 2011; 37:525.
  490. Hall MW, Greathouse KC, Thakkar RK, et al. Immunoparalysis in Pediatric Critical Care. Pediatr Clin North Am 2017; 64:1089.
  491. Cao W, Taylor AK, Biber RE, et al. Rapid differentiation of monocytes into type I IFN-producing myeloid dendritic cells as an antiviral strategy against influenza virus infection. J Immunol 2012; 189:2257.
  492. Costantini C, Calzetti F, Perbellini O, et al. Human neutrophils interact with both 6-sulfo LacNAc+ DC and NK cells to amplify NK-derived IFN{gamma}: role of CD18, ICAM-1, and ICAM-3. Blood 2011; 117:1677.
  493. Tillack K, Breiden P, Martin R, Sospedra M. T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J Immunol 2012; 188:3150.
  494. Chertov O, Yang D, Howard OM, Oppenheim JJ. Leukocyte granule proteins mobilize innate host defenses and adaptive immune responses. Immunol Rev 2000; 177:68.
  495. Kanda N, Kamata M, Tada Y, et al. Human β-defensin-2 enhances IFN-γ and IL-10 production and suppresses IL-17 production in T cells. J Leukoc Biol 2011; 89:935.
  496. Davidson DJ, Currie AJ, Reid GS, et al. The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J Immunol 2004; 172:1146.
  497. Niyonsaba F, Iwabuchi K, Matsuda H, et al. Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway. Int Immunol 2002; 14:421.
  498. Niyonsaba F, Iwabuchi K, Someya A, et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 2002; 106:20.
  499. Dudeck J, Froebel J, Kotrba J, et al. Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency. J Allergy Clin Immunol 2019; 143:1849.
  500. Andoniou CE, Andrews DM, Degli-Esposti MA. Natural killer cells in viral infection: more than just killers. Immunol Rev 2006; 214:239.
  501. Marcenaro E, Carlomagno S, Pesce S, et al. Bridging innate NK cell functions with adaptive immunity. Adv Exp Med Biol 2011; 780:45.
  502. Eisenberger NI, Cole SW. Social neuroscience and health: neurophysiological mechanisms linking social ties with physical health. Nat Neurosci 2012; 15:669.
  503. Cohen S, Alper CM, Doyle WJ, et al. Positive emotional style predicts resistance to illness after experimental exposure to rhinovirus or influenza a virus. Psychosom Med 2006; 68:809.
  504. Veiga-Fernandes H, Artis D. Neuronal-immune system cross-talk in homeostasis. Science 2018; 359:1465.
  505. Foster SL, Seehus CR, Woolf CJ, Talbot S. Sense and Immunity: Context-Dependent Neuro-Immune Interplay. Front Immunol 2017; 8:1463.
  506. Schiller M, Ben-Shaanan TL, Rolls A. Neuronal regulation of immunity: why, how and where? Nat Rev Immunol 2021; 21:20.
  507. Bordon Y. Immune cells freeze in response to stress signalling. Nat Rev Immunol 2021; 21:344.
  508. Zouikr I, Hasegawa-Ishii S, Shimada A. Editorial: Neuroimmune Interface in Health and Diseases. Front Immunol 2017; 8:1315.
  509. Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and Therapeutic Relevance of Neuro-immune Communication. Immunity 2017; 46:927.
  510. Salvador AF, de Lima KA, Kipnis J. Neuromodulation by the immune system: a focus on cytokines. Nat Rev Immunol 2021; 21:526.
  511. Kabata H, Artis D. Neuro-immune crosstalk and allergic inflammation. J Clin Invest 2019; 129:1475.
  512. Wang S, Quan L, Chavarro JE, et al. Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post-COVID-19 Conditions. JAMA Psychiatry 2022; 79:1081.
  513. Ben-Shaanan TL, Azulay-Debby H, Dubovik T, et al. Activation of the reward system boosts innate and adaptive immunity. Nat Med 2016; 22:940.
  514. Frost EL, Lukens JR. The brain's reward circuitry regulates immunity. Nat Med 2016; 22:835.
  515. Devi S, Alexandre YO, Loi JK, et al. Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses. Immunity 2021; 54:1219.
  516. Steinman L. Lessons learned at the intersection of immunology and neuroscience. J Clin Invest 2012; 122:1146.
  517. Russo MV, McGavern DB. Inflammatory neuroprotection following traumatic brain injury. Science 2016; 353:783.
  518. Norris GT, Smirnov I, Filiano AJ, et al. Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury. J Exp Med 2018; 215:1789.
  519. Thion MS, Ginhoux F, Garel S. Microglia and early brain development: An intimate journey. Science 2018; 362:185.
  520. Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med 2017; 23:1018.
  521. Underwood E. Wired. Science 2016; 353:762.
  522. Watanabe S, Sato K, Hasegawa N, et al. Serum C1q as a novel biomarker of sarcopenia in older adults. FASEB J 2015; 29:1003.
  523. Klein RS. On Complement, Memory, and Microglia. N Engl J Med 2020; 382:2056.
  524. Wang C, Yue H, Hu Z, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science 2020; 367:688.
  525. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature 2016; 530:177.
  526. Cannon TD, Chung Y, He G, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry 2015; 77:147.
  527. Zengeler KE, Lukens JR. Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders. Nat Rev Immunol 2021; 21:454.
  528. Cho H, Proll SC, Szretter KJ, et al. Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. Nat Med 2013; 19:458.
  529. Mashaghi A, Marmalidou A, Tehrani M, et al. Neuropeptide substance P and the immune response. Cell Mol Life Sci 2016; 73:4249.
  530. Suvas S. Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis. J Immunol 2017; 199:1543.
  531. Shields GS, Spahr CM, Slavich GM. Psychosocial Interventions and Immune System Function: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Psychiatry 2020; 77:1031.
  532. Alderton G, Scanlon ST. Inflammation. Science 2021; 374:1068.
  533. Medzhitov R. The spectrum of inflammatory responses. Science 2021; 374:1070.
  534. Hotamisligil GS. Foundations of Immunometabolism and Implications for Metabolic Health and Disease. Immunity 2017; 47:406.
  535. Loof TG, Mörgelin M, Johansson L, et al. Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense. Blood 2011; 118:2589.
  536. Doolittle RF. Clots vs bugs: who's ahead? Blood 2011; 118:2382.
  537. Doronin K, Flatt JW, Di Paolo NC, et al. Coagulation factor X activates innate immunity to human species C adenovirus. Science 2012; 338:795.
  538. Herzog RW, Ostrov DA. Immunology. A decorated virus cannot hide. Science 2012; 338:748.
  539. Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood 2016; 128:753.
  540. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13:34.
  541. Vaisar T, Pennathur S, Green PS, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007; 117:746.
  542. Reilly MP, Tall AR. HDL proteomics: pot of gold or Pandora's box? J Clin Invest 2007; 117:595.
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