INTRODUCTION — Mast cells display a host of stimulatory and inhibitory surface receptors, allowing them to respond to a variety of stimuli in a modulated manner. The ultimate response of a cell to its environment is determined by the balance of stimulatory and inhibitory factors present at a given moment and acting on different receptors.
This topic review will discuss the activating and inhibitory receptors on mast cells and signal transduction mechanisms. The information in this review pertains to human mast cells whenever possible, and notation is made when data are derived purely from murine studies. Mast cell-derived mediators, as well as the development, identification, and physiologic roles of mast cells, are reviewed separately. (See "Mast cell-derived mediators" and "Mast cells: Development, identification, and physiologic roles".)
ACTIVATING RECEPTORS — Important stimulatory receptors on the surface of mast cells include the high-affinity immunoglobulin E (IgE) receptor, immunoglobulin G (IgG) receptors, Toll-like receptors (TLRs), receptors for stem cell factor (SCF), complement proteins, cytokine receptors (eg, for the alarmins interleukin [IL] 33 and thymic stromal lymphopoietin [TSLP]), neuropeptides, and opioids. A G-coupled protein receptor that is important in non-IgE anaphylactic reactions, MRGPRX2, was identified in 2015 .
High-affinity IgE receptor — Classical mast cell activation occurs through the high-affinity IgE receptor, Fc-epsilon-RI. Activation occurs when adjacent receptors, occupied by receptor-bound IgE, are crosslinked by a multivalent antigen. This is a strong stimulus for degranulation and release of preformed mediators, as well as for de novo production and subsequent release of leukotrienes, prostaglandins, and cytokines, including numerous chemokines. (See "Mast cell-derived mediators".)
High- and low-valency or affinity antigens are able to trigger differential responses through Fc-epsilon-RI receptors. High-affinity or high-valency antigens trigger classic degranulation and cytokine responses with neutrophilic inflammation. In contrast, low-valency or low-affinity allergens may not trigger degranulation but can still trigger production of chemokines that recruit macrophages and monocytes [2,3].
IgE is involved in defense against parasitic infection and in hypersensitivity reactions. It is estimated that there are usually >100,000 Fc-epsilon-RI receptors on the surface of each human mast cell, although the number can vary with activation state and the presence of circulating IgE [4-6]. As the transcript is stabilized by binding of monomeric IgE to the receptor, there is a greater number of receptors and hence capacity for binding serum IgE in atopic individuals. This likely accounts for this large range in the number of receptors per cell and the efficacy of therapy directed to reducing the serum titer of IgE [7-9]. (See 'Clinical applications' below.)
The fully functional form of the Fc-epsilon-RI receptor on mast cells and on basophils is a tetrameric structure consisting of one alpha chain, one beta chain, and two gamma chains [10,11]:
●The alpha chain contains two extracellular domains that bind IgE with high affinity.
●The beta chain transverses the membrane four times and may form an ion pore.
●The two gamma chains, which are structurally homologous to the zeta chain of the T cell receptor, each have two cytoplasmic immunoreceptor tyrosine activation motifs (ITAMs) and mediate signal transduction.
Several other human cell types express a trimeric form of Fc-epsilon-RI, which lacks the beta chain. This is found on eosinophils, epithelial cells, and antigen-presenting cells, such as dendritic cells, Langerhans cells, and monocytes, and may be involved in the immune modulatory functions of these cells [10,12-16]. (See "Mast cells: Development, identification, and physiologic roles", section on 'Acquired immunity'.)
MRGPRX2 — A Mas-related G protein–coupled receptor, first described in 2015, may be responsible for reactions to quinolone medications, such as ciprofloxacin, vancomycin, icatibant, morphine, and general anesthetics, such as rocuronium, atracurium, and others with the central tetrahydroisoquinoline (THIQ) motif . While low concentrations of medications are sufficient to activate mast cells through the IgE receptor, much higher concentrations are needed for MRGPRX2 activation (EC50 varying from 22 to 260 mcg/mL) . Therefore, the plasma concentrations reached by many drugs that are ligands for MRGPRX2 might not be high enough to activate this receptor. Importantly, skin testing concentrations used for most medication skin tests would be too low to activate MRGPRX2 . The extent of the expression of this receptor on human mast cells is not fully understood, although it could potentially explain anaphylactic reactions to these medications in which IgE antibodies have not been demonstrated.
MRGPRX2 is also expressed on human basophils and eosinophils .
Studies in mice point to a role of the mouse ortholog of MRGPRX2 (Mrgprb2) in nonhistaminergic itch and in mast cell–sensory neuron interactions [19,20]. Whether MRGPRX2 mediates similar reactions in humans has not been established. However, a significant increase in number and percentage (45 versus 22 percent) of MRGPRX2 mast cells has been described in the skin of patients with chronic urticaria compared with that of nonatopic control subjects . In addition, cutaneous mast cells of patients with chronic urticaria show increased reactivity to MRGPRX2 ligands .
Receptors for mechanical stimulation — Mast cell degranulation in response to mechanical stimulation was linked to signaling through the dermatan sulfate adhesion GPCR, ADGRE2. Mutations of ADGRE2 that render it "hyperactive" are associated with a vibratory urticaria phenotype [23,24]. (See "Physical (inducible) forms of urticaria", section on 'Vibratory angioedema and urticaria'.)
IgG receptors — Human mast cells also express receptors for IgG, including Fc-gamma-RII-alpha and Fc-gamma-RIII, activating receptors that bind IgG3 most avidly [25,26]. These receptors allow activation of the cells by immune complexes that are either circulating or formed in situ. Human mast cells can also transiently express Fc-gamma-RI, another activating receptor .
Kit (stem cell factor receptor) — Mast cells express Kit, the receptor for SCF, which is the critical growth factor for mast cell development. (See "Mast cells: Development, identification, and physiologic roles", section on 'Kit and stem cell factor'.)
For mature mast cells, SCF also serves as a chemotactic factor and can be a direct activator, causing degranulation and cysteinyl leukotriene production, and, in conjunction with IL-10 and IL-1-beta, can be an inducer of prostanoid and cytokine production [28-34].
Alarmin receptors — Mast cells express the IL-33 receptor known as ST2, which is a member of the IL-1 receptor family as well as a receptor for the alarmin TSLP . Both of these can be released from activated epithelium. The epithelium releases an alternatively spliced form of IL-33, which, in combination with TSLP, activates mast cells. This pathway is likely important in various responses occurring at environmental interfaces. For instance, together with basophils, this pathway for mast cell activation has been implicated in driving the type 2 inflammation in some patients with asthma  and in patients with aspirin-exacerbated respiratory disease [37,38]. TSLP-mediated activation of mast cells triggers prostaglandin D2 (PGD2) production and likely contributes significantly to the non-IgE-mediated aspirin-induced reactions in patients with aspirin-exacerbated respiratory disease .
Complement receptors — Mast cells in human skin express receptors for both the anaphylatoxins, C3a and C5a, and release histamine in response to exposure to these complement fragments. These provide additional mechanisms in which immune complexes or microbes may activate mast cells that may occur via classical or alternative complement activation pathways. However, in contrast to activation through Fc-epsilon-RI, exocytosis by complement fragments is not associated with the generation of prostaglandins or leukotrienes. There is some variability in distribution of complement receptors as some cardiac mast cells demonstrate a functional receptor for C5a (CD88) by immunofluorescence, whereas mast cells isolated from the human lung, uterus, or tonsils do not [40-43]. (See "Complement pathways", section on 'Classical pathway'.)
Toll-like receptors — Mast cells express a variety of TLRs, which are both surface and internal membrane-associated molecules in eukaryotic cells that detect and respond to microbial infection. The activation of mast cells through TLRs is an important mechanism through which mast cells serve as a bridge between the innate and adaptive immune systems. Using cultured human mast cell lines, these cells have been shown to express TLRs 1 through 9, although TLR8 was lost with continued culture [44-46].
Human mast cells also can be activated by many of the ligands specific to the different receptors (eg, peptidoglycans through TLR2, double-stranded ribonucleic acid [RNA] through TLR3, and lipopolysaccharide [LPS] through TLR4). In broad terms, mast cells respond to activation through TLR with the production of inflammatory cytokines, rather than degranulation, yet the responses to the different stimuli are distinct. Thus, double-stranded RNA induces expression of the type 1 interferons, but not tumor necrosis factor (TNF) alpha or IL-6, while LPS induces expression of these two proinflammatory cytokines, but not degranulation as occurs following peptidoglycan stimulation [47,48]. A general discussion of TLRs is found elsewhere. (See "Toll-like receptors: Roles in disease and therapy".)
Receptors for neuropeptides and opioids — Neuropeptides, such as vasoactive intestinal polypeptide (VIP), substance P, and somatostatin, mediate secretory granule exocytosis from mast cells with little generation of lipid mediators [49-51]. The responses to these neuropeptides are mediated through pertussis-sensitive G proteins, with concomitant release of calcium from intracellular stores [52-54]. Mast cell activation by substance P is at least partially mediated through MRGPX2 .
Certain muscle relaxants, such as succinylcholine, tubocurarine, and atracurium, cause both skin and lung mast cells to release histamine, while opiates also cause histamine release from skin mast cells [56-58]. The latter underlies the common occurrence of pruritus and urticaria in response to opioid analgesics.
Platelet-activating factor receptor — Receptors for platelet-activating factor (PAF) have been identified on human mast cells cultured from the lung and from progenitors in peripheral blood . PAF is known to be important in murine anaphylaxis, and preliminary data suggest that PAF plays a role in human anaphylaxis as well, particularly in amplification of the initial response. (See "Pathophysiology of anaphylaxis", section on 'Chemical mediators of anaphylaxis'.)
INHIBITORY RECEPTORS — Mast cells express several inhibitory receptors. While the functions of these are not fully understood, some have been shown to regulate mast cell-mediated events including human mast cell activation, and, in the mouse, mast cell-dependent inflammation [60,61]. Many of the inhibitory receptors contain immunoregulatory tyrosine inhibition motifs (ITIMs).
Examples of ITIM-associated receptors capable of suppressing mast cell activation are Fc-gamma-RIIb, CD300a, platelet-endothelial cell adhesion molecule 1 (PECAM-1), paired immunoglobulin-like receptor B (PIR-B), the c-lectin mast cell function-associated antigen (MAFA), sialic acid-binding immunoglobulin-like lectins (Siglecs), and leukocyte immunoglobulin-like receptor 4, subfamily B, member 4 (LILRB4) [61,62]. PIR-B is a surface receptor expressed on both mast cells and macrophages and appears to regulate basal activation of both cells. Examples of ITIM-independent inhibitory receptors include the mast cell receptor for the glycoprotein CD200, the A2b adenosine receptor, and the transient receptor potential cation channel, subfamily M, member 4 (TRPM4) ion channel .
Siglecs — Sialic acid-binding immunoglobulin-like lectin (Siglec) 6 and Siglec-8 are expressed on mast cells and eosinophils, and therapeutic targeting of Siglec 8 is under investigation for treatment of diseases of mast cell expansion and activation [63-66].
Leukocyte immunoglobulin-like receptor 4 — Murine mast cells express LILRB4, an inhibitory receptor with significant homology with the killer cell inhibitory receptors (KIR) found on natural killer (NK) cells [56,67,68]. This molecule was previously called gp49B1. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)
Mice deficient in LILRB4 have increased severity in local and systemic anaphylaxis, suggesting that this receptor has a "braking function" during mast cell activation [68,69].
CD200 receptor 1 — The CD200 R1 receptor, a member of the immunoglobulin supergene family that is expressed on myeloid cells, inhibits mast cell degranulation and cytokine secretion [70-72]. It does not contain an ITIM and may play a role in determining the cell's threshold for activation. In contrast, a related member of this family, CD200 R3, has been implicated in mast cell activation .
CD300a — CD300a is a type 1 transmembrane protein that contains three classical and one nonclassical ITIM in the intracellular cytoplasmic tail. It is expressed on both myeloid and lymphoid cells. Coligation of the high-affinity IgE receptor and CD300a inhibits mast cell activation [74-77].
Beta-adrenoreceptor 2 — The beta-adrenoreceptor (beta-2) found on human lung mast cells is linked via a G protein to a cyclic AMP (cAMP) dependent pathway of calcium mobilization . Isolated human lung mast cells display inhibition of degranulation and eicosanoid generation after treatment with beta agonists [79,80].
IgG receptors — The IgG receptor Fc-gamma-RIIb is an inhibitory receptor on the surface of mast cells. Fc-gamma-RIIb crosslinking has been shown to reduce IgE-mediated mast cell activation, and investigational therapies based on this mechanism have been reported [81,82].
Toll-like receptor 4 — Toll-like receptor (TLR) 4 also binds a protein produced by parasitic roundworms, ES-62 . Unlike the binding of TLR4 to lipopolysaccharide (LPS), however, ligation with ES-62 results in inhibition of activation of the cell through Fc-epsilon-RI, and, therefore, TLR4 functions as an inhibitory receptor in this context . Nematodes expressing this protein would be able to modulate the mast cell inflammatory response of the host to infection, thus preventing fulminant inflammation and demise of the host or expulsion of the parasite. Future therapies based upon analogs of ES-62 have been proposed. (See "Toll-like receptors: Roles in disease and therapy".)
SIGNAL TRANSDUCTION — Signal transduction pathways are intertwined webs of molecules through which external information about ongoing events is transmitted to the internal workings of that cell in order to induce a specific effect. These pathways are complex, overlapping, and tightly controlled. The steps in the signal transduction pathway that results from crosslinking of two Fc-epsilon-RI receptors by multivalent antigen on the surface of a mast cell are described here as an example:
●Crosslinking of the Fc-epsilon-RI receptor by polymeric/polyvalent antigens bound to specific IgE at the membrane initiates signal transduction. Specific IgE is bound to the alpha chain of the Fc-epsilon-RI, while the beta and gamma chains are critical for signal transduction. (See 'High-affinity IgE receptor' above.)
●Crosslinking of Fc-epsilon-RI leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of the cytoplasmic domain of both the beta and gamma subunits of the receptor complex . The beta chain of Fc-epsilon-RI is constitutively associated with Lyn, a tyrosine kinase belonging to the Src family [85,86]. Tyrosine phosphorylation of the beta subunit activates Lyn . Activated Lyn mediates recruitment of the nonreceptor tyrosine kinase Syk, which interacts via its SH2 domain with the phosphorylated ITAM on the gamma subunit of Fc-epsilon-RI [85,87,88]. Syk then stimulates sequences leading to the mitogen-activated protein kinase (MAPK) pathways and the protein kinase C (PKC) and Ca2+ dependent pathways .
●Activation of the MAPK pathway has been linked to the downstream activation of cytosolic phospholipase A2 (cPLA2) in stimulated mast cells [90-93]. The enzyme cPLA2 translocates from a cytosolic to membrane compartment , where it cleaves arachidonic acid from phospholipids for the generation of leukotrienes and prostaglandins, as well as forming lyso-phosphatidylcholine, the precursor of platelet-activating factor (PAF).
●Syk phosphorylation also causes activation of phosphatidylinositol-specific phospholipase C (PLCg1). The activated PLC cleaves phosphatidylinositol-derived inositol 4,5 bisphosphate (PIP2) to generate the second messengers diacylglycerol (DAG) and inositol 1,4,5 triphosphate (IP3) [95,96]. DAG activates PKC with a consequent translocation to the plasma membrane.
●PKC activation results in phosphorylation of numerous proteins including the myosin light chain, which is thought to contribute to exocytosis of mast cell granules and the activation of c-fos and c-jun, leading to enhanced transcription of immediate early genes [97,98]. IP3 acts at the endoplasmic reticulum to release calcium from intracellular stores and activates the calmodulin/calcineurin phosphatase pathway with resultant transcription of cytokine genes, such as interleukin (IL) 6, via the nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT) [99,100]. Subsequent influx of calcium through the membrane further augments mast cell degranulation .
●Early activation events lead to the release of granule contents, arachidonic acid metabolites, and tumor necrosis factor (TNF) alpha secretion. Late-phase events include the release of cytokines and chemokines, such as IL-1-beta, IL-6, and newly formed TNF-alpha. (See "Mast cell-derived mediators".)
CLINICAL APPLICATIONS — Activating and inhibitory receptors on mast cells and the signaling pathways used by these receptors can be manipulated to achieve specific clinical effects. The following are examples of therapeutic applications that have either already been realized or are in development:
●The high-affinity IgE receptor can be downregulated on the surface of mast cells by administration of the anti-IgE therapy omalizumab. This agent binds free IgE in the serum and tissues and clears it from circulation, resulting in a reduction in the number of Fc-epsilon-RI receptors present on mast cells (and basophils). Anti-IgE therapy is used in the treatment of allergic asthma. It has also been successfully administered to patients with Hymenoptera venom-induced anaphylaxis who require venom immunotherapy but who have reactions to the injections to improve the safety of the vaccination process. In the future, its use may be extended to other diseases in which IgE is part of the pathophysiology, including allergic rhinitis and anaphylaxis. The use of anti-IgE therapy in asthma and chronic idiopathic urticaria is reviewed in more detail separately. (See "Anti-IgE therapy".)
●The receptor for stem cell factor (SCF), Kit, is a tyrosine kinase. PKC412 (midostaurin) is a tyrosine kinase inhibitor that inhibits Kit, including Kit with a specific D816V mutation, while imatinib inhibits only wild-type Kit. Patients with aggressive forms of systemic mastocytosis have benefited from these drugs, providing evidence that activation of Kit is a fundamental part of the pathophysiology of the disease. Patients with severe refractory asthma improve with imatinib, and their lung mast cell numbers decrease . (See "Advanced systemic mastocytosis: Management and prognosis", section on 'Midostaurin'.)
●Analogs of the parasite product ES-62, an agonist of Toll-like receptor (TLR) 4, are in development. The action of ES-62 at TLR4 leads to inhibition of Fc-epsilon-RI. It is hoped that these agents could be used as immunomodulators to treat or prevent allergic and other inflammatory diseases [103,104]. (See "Toll-like receptors: Roles in disease and therapy", section on 'TLR-based therapies'.)
●Fusion proteins composed of major allergenic proteins linked to agonists of inhibitory IgG receptors have been developed for the purposes of treating allergic disease. For example, the major cat allergen, Fel d 1, has been fused with Fc-gamma-I and is being studied for use in safer and more effective forms of immunotherapy .
●Syk inhibitors have been studied to block signal transduction in mast cells and prevent activation at the time of allergen exposure, and their application in allergic rhinitis and asthma is under study. However, the potential side effects of blocking signal transduction are complex due to the broad functions of Syk in T cells and other immune cells.
●Mast cells have many different stimulatory and inhibitory receptors – Mast cells display a host of stimulatory and inhibitory surface receptors, and the balance of signals arising from these receptors at a given moment determines the ultimate response of the cell. (See 'Introduction' above.)
●Important stimulatory receptors – Important stimulatory mast cell receptors include the high-affinity immunoglobulin E (IgE) receptor, immunoglobulin G (IgG) receptors, MRGPRX2, Toll-like receptors (TLRs), complement component receptors, and the receptor for stem cell factor (SCF). (See 'Activating receptors' above.)
●Important inhibitory receptors – Inhibitory receptors act to regulate and modulate mast cell function. Critical inhibitory receptors include leukocyte immunoglobulin-like receptor, subfamily B, member 4 (LILRB4) and CD200R1. (See 'Inhibitory receptors' above.)
●Signal transduction – Signal transduction pathways are complex and precisely controlled networks of molecules, through which information is transmitted from the cell surface to the inside of the cell to induce a specific effect. (See 'Signal transduction' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
The UpToDate editorial staff acknowledges Michael Gurish, PhD, who contributed to earlier versions of this topic review.
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