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Mast cell-derived mediators

Mast cell-derived mediators
Authors:
Mariana C Castells, MD, PhD
Lora Bankova, MD
Section Editor:
Sarbjit Saini, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: May 26, 2022.

INTRODUCTION — Mast cells release various mediators upon activation, which are responsible for many of the systems of allergic disease and anaphylaxis. These mediators can be divided into three overlapping categories: preformed mediators, newly synthesized lipid mediators, and cytokines and chemokines.

This topic will review mast cell mediators. The information in this topic pertains to human mast cells whenever possible, and notation is made when data are derived purely from murine studies. The development, physiologic roles, surface receptors, and signal transduction of mast cells are reviewed separately. (See "Mast cells: Development, identification, and physiologic roles" and "Mast cells: Surface receptors and signal transduction".)

PREFORMED MEDIATORS — Mast cell secretory granules contain preformed mediators that are rapidly (within seconds to minutes) released into the extracellular environment upon cell stimulation. These mediators include histamine, neutral proteases, proteoglycans, and some cytokines, such as tumor necrosis factor-alpha (TNF-alpha). They are responsible for many of the acute signs and symptoms of mast cell-mediated allergic reactions, including edema, bronchoconstriction, and increased vascular permeability. Specific pharmacotherapy to inhibit and/or antagonize mast cell mediators is reviewed elsewhere.

Histamine — Histamine is produced predominantly by mast cells but also is elaborated by basophils, neutrophils [1], and platelets. It is stored in both scroll-like and lattice secretory granules of the human mast cell [2]. Human cutaneous mast cells are estimated to contain 1.9 micrograms of histamine per 106 cells [3]. Secretory granule exocytosis and release of histamine occurs rapidly after either immunoglobulin E (IgE)- or non-IgE-based stimulation [4]. The effects of histamine are mediated through H1, H2, H3, and H4 receptors located on target cells:

H1-mediated actions include increased venular permeability, bronchial and intestinal smooth muscle contraction, increased nasal mucus production, widened pulse pressure, increased heart rate and cardiac output, flushing, and T cell neutrophil and eosinophil chemotaxis [5,6]. In mice, lack of H1 receptors leads to reduced lung inflammation as a consequence of the decreased T cell influx [6].

The effects mediated through the H2 receptor include increased venular permeability, increased gastric acid secretion, and airway mucus production but inhibition of neutrophil and eosinophil influx [7,8].

An H3 receptor has been located in the brain, as well as on sympathetic nerve fibers innervating blood vessels in the nasal mucosa and heart, although its precise role is not fully characterized [9,10].

An H4 receptor has been identified and cloned in both mice and humans [11,12]. This receptor modulates T helper type 2 (Th2) responses, and H4-deficient mice have decreased lung inflammation with less infiltration of eosinophils and lymphocytes [13]. Acting through the H4 receptor, histamine can act as a chemoattractant for mouse bone marrow-derived mast cells and modulate calcium influx [14]. In humans, the actions of histamine at the H4 receptor provide a potent chemotactic pathway for human eosinophils [15].

Serotonin — Human mast cells produce the biogenic amine serotonin during fetal development and possibly under some conditions in adult life [16,17]. Human fetal periodental mast cells produce and store serotonin in high amounts, coinciding with the appearance of enameloblasts [16].

Proteoglycans — The metachromatic staining of mast cell granules is due to sulfated, anionic proteoglycans, such as heparin and chondroitin sulfate. These are composed of a peptide core, serglycin, to which is added the complex glycosaminoglycans [18,19].

Heparin may serve to stabilize the multimeric complex of histamine, proteoglycan, and active neutral proteases within the secretory granule [20]. With granule exocytosis, heparin retains many of the proteases in the macromolecular complex [21-23]. Heparin also functions as an anticoagulant, inhibits the complement cascade, and markedly potentiates the action of angiogenic factors, such as basic fibroblast growth factor [24-29].

Chondroitin sulfate-E, a highly sulfated proteoglycan like heparin, has kinin pathway activation effects and protease-stabilizing functions [30].

Tryptases and other proteases — Important mast cell proteases include the tryptases, chymases, cathepsin G, renin, and a mast cell-specific carboxypeptidase A [20].

Tryptases — Tryptases are the most abundant proteases of the human mast cell, comprising up to 20 percent of the cell protein [3,31,32]. Some human mast cells contain up to 35 micrograms of tryptase/106 cells, which is a dramatically higher protease content than any other granulocyte. The other cell type that contains some tryptase, the basophil, has only very low levels (0.4 percent of the tryptase in mast cells) [33]. Thus, serum tryptase is a relatively specific marker of mast cell degranulation/activation. The demonstration that a mast cell-mediated event has occurred is important in the diagnosis of mast cell disorders, anaphylaxis, and drug-allergic reactions. (See "Mast cell disorders: An overview" and "Anaphylaxis: Acute diagnosis", section on 'Laboratory tests' and "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Laboratory tests at the time of the reaction'.)  

Two forms of tryptase are used clinically: Total tryptase and mature tryptase. Total tryptase levels are detectable in normal donors at serum levels of up to 15 ng/mL and reflect total body mast cell content. Persistent elevations in total tryptase in excess of 20 ng/mL are indicative of systemic mastocytosis. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

By comparison, mature active tryptase is stored within the secretory granule and released only during exocytosis [34]. It requires the heparin proteoglycans for activity [20]. Serum levels of this form of tryptase are normally undetectable (<1 ng/mL). The normal ratio between total and mature tryptase is usually less than 20 [33].

Mature tryptase serves as a useful marker of mast cell degranulation, as it is a product nearly exclusive to mast cells. Elevations of mature tryptase may be observed during acute anaphylactic events involving severe symptoms and hypotension, rising within 15 minutes and detectable by 30 to 60 minutes after the event. Elevations can persist for several hours, depending upon the magnitude of the initial rise and can be associated with elevations of total tryptases. Elevations in mature beta tryptase can be used to confirm the diagnosis of anaphylaxis, although levels might not rise during food-induced anaphylaxis, possibly reflecting differences in the pathophysiology of these forms of anaphylaxis [35]. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

Tryptase levels in the bronchoalveolar fluid correlate with asthma severity and in severe asthma, this correlation is independent of biomarkers of type 2 inflammation such as eosinophil and periostin levels. Genetic alleles that increase the activity of tryptase decrease the response to treatment with omalizumab [36]. This finding suggests that anti-tryptase drugs could be developed for severe asthma in the future.

Functions — The tryptases are serine-endopeptidases that exhibit trypsin-like activity and cleave after basic amino acid residues in the proteins [37]. They are cationic tetrameric proteins that form a macromolecular complex with heparin proteoglycan [38]. These complexes are distinct from those containing chymase and carboxypeptidase, implying separate pathways of protease processing [22].

Tryptase has been shown to have many actions in vitro, although the relative importance of these remains unclear [20]. These actions include:

Inactivation of fibrinogen and inhibition of fibrinogenesis, with anticoagulant activity that exceeds that of heparin. Beta tryptase, which is enzymatically active upon release from granules, degrades the alpha chain of fibrinogen and prevents its activation [39,40]. This may explain why some patients with anaphylaxis or mastocytosis develop hemorrhagic disorders (eg, abnormal intraoperative bleeding) and why children with diffuse cutaneous mastocytosis can bleed into the blisters.

Activation of tissue matrix metalloproteinases (MMP), including prostromelysin (MMP-3), which activates collagenase of rheumatoid synovial cells [41].

Inactivation of certain neuropeptides including the bronchodilatory vasoactive intestinal peptide (VIP) [42,43].

Stimulation of fibroblast proliferation and mRNA synthesis for procollagen in human culture systems [44,45].

Chemotactic activity for eosinophils [46]. Recruitment of eosinophils contributes to the late phase of an allergic reaction (or allergen challenge), which is important in disorders such as asthma. (See "Pathogenesis of asthma", section on 'Early and late phase reactions'.)

Upregulation of interleukin 8 (IL-8) synthesis and intercellular adhesion molecule-1 (ICAM-1) expression in bronchial epithelial cells [47].

A pruritogenic effect of tryptase has been found in mice through the proteinase-activated receptor-2 (PAR2) receptor [48]. Human mast cells also have PAR2 receptors, although further study in humans is needed.

Tryptase catalytic activity can trigger mast cell degranulation in a feedforward manner [36].

Several human mast cell phenotypes are delineated based upon the relative content of tryptase, chymase, and the mast cell-specific carboxypeptidase, CPA3 [3]:

MCTC (mast cells containing tryptase and chymase) – Contain both tryptase (in the greatest amounts) and chymase (skin and intestinal submucosa) and are the predominant type of MC found in connective tissue locations like the skin and around blood vessels. In the inflamed nasal tissue of patients with chronic rhinosinusitis, the MCTC acquire a pro-inflammatory phenotype with increased expression of chemokines (CCL2, CCL3, CCL4), growth factors (CSF1 and CSF2), and COX2 [49].

MCT (mast cells containing tryptase) – Contain tryptase but little chymase (mucosal tissues) and are associated with inflammation and found mostly in mucosa in the lung and intestine. Of note, this phenotype is T cell-dependent and is lost in patients with acquired immunodeficiency syndrome (AIDS) [50].

Although MCTs are the predominant epithelial phenotype associated with recruited mast cells in the setting of allergic inflammation, mast cells expressing both chymase and tryptase are found in the epithelium of patients with severe asthma, suggesting a switch in phenotype with more severe disease [51,52].

MCC (mast cells containing chymase) – Contain only chymase and are found in the intestine.

MCT-CPA (mast cells containing carboxypeptidase A) are a mucosal phenotype found in eosinophilic esophagitis and a subgroup of asthmatics characterized with high T helper type 2 (Th2) activity [53,54]. This subgroup contains only tryptase and CPA with little or no chymase. MCT-CPA are dramatically increased in polyps of patients with chronic rhinosinusitis. They notably also express IL17RB, the receptor for the cytokine IL-25 [49].

Carboxypeptidase A — Mast cell carboxypeptidase A (CPA3) may be the most specific mast cell marker identified, as it has not been identified in basophils, unlike tryptase. However, it is not readily found in serum and thus is not a marker that can be used to identify mast cell activation, except within tissue sections. It is primarily localized within the MCTC subset in gut submucosa and in skin [55-57]. Human foreskin mast cells are estimated to contain 16 micrograms of CPA per106 cells [58].

This exopeptidase is functionally similar to pancreatic carboxypeptidase B, even though it is more similar to pancreatic carboxypeptidase A by amino acid sequence. It functions at neutral to basic pH to cleave carboxy-terminal aliphatic and aromatic amino acids from proteins after their exposure to chymotryptic proteases [59]. CPA3 functions to convert angiotensin I to angiotensin II [59] and has been shown to degrade neuropeptides [60]. It may also degrade some toxins, such as those in bee and snake venoms [61,62].

Chymase — The MCTC (and rare MCC) subpopulations of human mast cells contain the chymotrypsin-like serine endopeptidase chymase and/or a second member of this gene family, cathepsin-G [55,57,59,63]. Cathepsin-G is also found in human neutrophils and eosinophils.

Mast cell chymase has the following activities:

A 100-fold greater potency in the conversion of angiotensin I to angiotensin II, compared with angiotensin-converting enzyme (ACE) [64]

Inactivation of bradykinin and the neuropeptides VIP and substance P [65,66]

Cleavage of laminin, type IV collagen, and fibronectin with attendant basement membrane degradation [67]

Converting the precursor of interleukin 1b (IL-1b) to an active form and stimulating secretion from airway serous cells [68,69]

Renin — Renin is a protease produced predominantly by juxtaglomerular cells in the kidney. However, significant local production of renin is also provided by cardiac mast cells [70,71]. Thus, mast cells provide both renin and ACE activity through chymase, both of which activate the renin-angiotensin system. It remains unclear whether this mechanism represents a protective response or if it contributes to ischemia-reperfusion injuries and predisposes to cardiac arrhythmias [72,73].

NEWLY SYNTHESIZED LIPID MEDIATORS — Mast cells utilize membrane phospholipids as a source of arachidonic acid for the synthesis of prostaglandins (PG), leukotrienes (LT), and platelet-activating factor (PAF) [74]. These inflammatory mediators are referred to as eicosanoids (ie, derived from arachidonic acid). The production of these mediators is initiated when phospholipase (PL) A2 enzymes release arachidonic acid from phospholipids. Arachidonate is converted to the intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and then to the epoxide, LTA4, by 5-lipoxygenase (5-LO). Subsequent conversion into the cysteinyl leukotriene LTC4 is achieved by LTC4 synthase or to the dihydroxy leukotriene LTB4 by LTA4 hydrolase [75].

Lipid mediators are formed de novo from membrane phospholipids after cell activation. In contrast to the preformed mediators, which are released immediately by exocytosis, lipid mediators appear more slowly, generally from 15 minutes to hours after activation, leading to their initial name of "slow reactive substance of anaphylaxis" (SRS-A). As a group, they are responsible for some of the signs and symptoms of allergic reactions, such as airflow obstruction, as well as leukocyte and dendritic cell recruitment. Not all degranulating stimuli will result in eicosanoid generation. Anaphylatoxins and neuropeptides activate mast cells in such a manner that minimal eicosanoids are produced [76-78].

Prostaglandins — Prostaglandin D2 (PGD2) is the principal prostaglandin produced by mast cells, and it has been recognized in bronchial or nasal secretions after allergen challenge [79,80]. The robust production of this mediator by mast cells makes it another good signature of mast cell activation. Its metabolite (9-alpha, 11-beta-PGF2) appears in the urine of patients with systemic mastocytosis and in aspirin-induced asthma [81,82]. Further support for its role in allergic reactions comes from mice lacking the PGD2 receptor, DP1, which showed decreased airway reactivity in a murine asthma model [83]. Salicylate therapy can be used to control PGD2 biosynthesis in these conditions. However, due to idiosyncratic responses to low doses of acetyl salicylate, such therapy must be initiated in a protected setting [82,84]. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Aspirin-exacerbated respiratory disease".)

Intradermal injection of PGD2 leads to a wheal-and-flare response due to vasodilation and increased vasopermeability [85], and inhalation of PGD2 causes airway smooth muscle bronchoconstriction [86]. PGD2 has been shown to inhibit platelet aggregation, be chemotactic for neutrophils, and activate eosinophils [87-89]. PGD2 has a potent sleep-inducing function, and when measured in rat cerebrospinal fluid, it was shown to have a circadian rhythm with elevated levels during sleep deprivation [90]. Whether mast cells contribute to brain levels of PGD2 is not known. Flushing in response to the drug niacin is mediated by PGD2 [91]. This adverse effect of niacin and measures to block PGD2 are reviewed separately. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (niacin)'.)

Human mast cells from different tissues have variable capacities to generate eicosanoids. PGD2 and LTC4 appear to be generated in approximately equal amounts by mast cells from skin or lung in response to activation by immunoglobulin E (IgE) and antigen, whereas lung mast cells generate 10-fold more LTC4 than PGD2 [73,92].

Cysteinyl leukotrienes — Activated human mast cells produce the parent of the cysteinyl leukotrienes, LTC4, along with far lesser amounts of LTB4 [93]. The production of LTB4 by mouse mast cells has been implicated in the specific recruitment of T cells to the lung with allergic inflammation [94,95]. LTC4 undergoes carrier-mediated export and subsequent extracellular conversion to the receptor active metabolites, LTD4 and LTE4 [96]. Cysteinyl leukotrienes exert their effect through activation of three distinct receptors:

Cysteinyl leukotriene receptor 1 (CysLT1R) is the high affinity receptor for LTD4 and binds LTC4 and LTE4 with lesser affinity. CysLT1R mediates cysteinyl leukotriene-dependent smooth muscle constriction and is inhibited by the CysLT1R inhibitors montelukast, zafirlukast, pranlukast.

CysLT2R is resistant to montelukast and other CysLT1R antagonists and binds LTC4 and LTD4 equally. CysLT1R and CysLT2R are broadly expressed by structural and hematopoietic cells, including mast cells.

CysLT3R, also called OXGR1 or GPR99, is a high-affinity receptor for LTE4 and is predominantly an epithelial cell receptor [97].

The cysteinyl leukotrienes increase microvascular permeability and are potent inducers of long-lasting wheal-and-flare responses [98]. Upon inhalation, they elicit bronchoconstriction in normal subjects with more than 1000-fold greater potency than histamine [99,100]. Levels of cysteinyl leukotrienes or their metabolites are elevated in nasal secretions in allergic rhinitis, bronchoalveolar lavage and urine from asthmatics under various circumstances, and in venous effluent elicited from cold urticaria [101-104]. LTE4 may also be an autocrine factor for mast cells, increasing cell proliferation, survival, and secretion of PGD2 [105-107].

Drugs that block the production of cysteinyl leukotrienes (zileuton) or block the actions of these compounds at the receptor level (montelukast, zafirlukast, and others) are used in the management of asthma, allergic rhinitis, and some forms of drug hypersensitivity. (See "Antileukotriene agents in the management of asthma".)

Platelet-activating factor — Platelet-activating factor (PAF) is produced and secreted by stimulated mouse and human mast cells through the action of the enzyme phospholipase A2 [108,109]. PAF acts through a specific receptor to chemoattract eosinophils, neutrophils, monocytes, and macrophages [110-112] and to stimulate macrophage cytokine production [113]. At a tissue level, PAF causes bronchoconstriction and vasopermeability [114]. Endothelial PAF interacts with neutrophils, leading to changes in their integrin expression with binding to intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell, thereby promoting neutrophil attachment and transmigration [115].

Deficiencies of PAF acetylhydrolase, an enzyme that inactivates PAF, have been linked to asthma in certain populations, as well as to severe anaphylaxis [116,117]. The PAF antagonist, Y24180, has been shown to improve pulmonary function in some asthmatics [118]. (See "Pathophysiology of anaphylaxis".)

CYTOKINES AND CHEMOKINES — The mast cell is increasingly recognized as a source of multifunctional cytokines that may participate in the recruitment and activation of other cells in the inflammatory microenvironment [119]. Mast cells with different secretory granule protease phenotypes exhibit differences in their cytokine profiles, thereby indicating further heterogeneity depending on tissue localization [120].

The mast cell is a source of T helper type 2 (Th2) cytokines, which are believed important in the perpetuation of the allergic response. Both human MCT (mast cells containing tryptase) and MCTC (mast cell containing tryptase and chymase) demonstrate transcripts and immunoreactive protein for interleukin 4 (IL-4) in situ [120,121], and cultured human lung mast cells release IL-4 after activation with immunoglobulin E (IgE) and antigen [122].

Interleukin-4 — Interleukin 4 (IL-4) is implicated in the development and upregulation of Th2 cells, is required for the biosynthesis of IgE, and stimulates the production of cysteinyl leukotrienes in a positive feedback loop that results in reactive mast cell hyperplasia [105].

Interleukin-5 — Human lung mast cells release interleukin 5 (IL-5) when activated ex vivo through the high affinity IgE receptor, Fc-epsilon-RI. IL-5 is a potent eosinophil maturation and cytoprotective factor [123]. Cultured human bone marrow-derived mast cells release Granulocyte-macrophage colony-stimulating factor (GM-CSF) after activation through Fc-epsilon-RI [124].

Interleukin-9 — Interleukin 9 (IL-9), originally identified as a T cell and mast cell growth factor, is produced concomitantly with other Th2 cytokines by CD4+Th2 cells [125]. IL-9 producing mast cells are recruited to the intestine in an experimental model of food allergy [126]. IL-9 and mast cell transcripts are increased in the intestine of atopic patients with food allergy [126].

Interleukin-33 — Interleukin-33 is an alarmin that is implicated in several disorders, including atopic diseases. There is some evidence that blocking IL-33 improves skin inflammation in atopic dermatitis [127].

TNF-alpha — Tumor necrosis factor-alpha (TNF-alpha, cachexin) was the first cytokine localized in human mast cells [128]. Some TNF-alpha may be constitutively stored in the granule, but the vast majority is induced with immunologic activation [129]. Studies using mast cell-deficient mice have demonstrated the importance of the mast cell-derived TNF-alpha in neutrophil recruitment in bacterial peritonitis, in protection from endotoxic shock, and in driving the initial immune response by directing antigen-presenting cell (dendritic cell) migration to local draining lymph nodes [130-132]. Mast cell-derived TNF-alpha also upregulates expression of endothelial adhesion molecules, such as endothelial-leukocyte adhesion molecule-1 (ELAM-1) and ICAM-1, facilitating adhesion and ingress of eosinophils and T cells to the inflammatory locus [133,134]. TNF-alpha derived from mast cells also may underlie lymph node hypertrophy in response to bacterial inflammation [135].

TGF-beta — Transcripts for transforming growth factor-beta (TGF-beta), a potent fibroblast activator and proliferation factor, are localized in human mast cells from fibrotic lung and rheumatoid synovium [136].

Chemokines — Mast cells release a number of chemokines, including the CC chemokine macrophage chemotactic protein-1 (MCP-1 or CCL2) and the CXC chemokine interleukin 8 (IL-8), which promotes neutrophil chemotaxis [137-139]. Transcripts for interleukin 1b (IL-1b), interleukin-13 (IL-3), and platelet-derived growth factor (PDGF) can be induced in the human mast cell line 1 (HMC-1), and studies in the mouse have implicated mast cell-derived IL-1 as critical to inflammatory joint disease [140,141].

SUMMARY

Types of mast cell mediators – Mast cells release a wide variety of mediators upon activation. These mediators can be divided into three overlapping categories: preformed mediators, newly synthesized lipid mediators, and cytokines and chemokines. (See 'Introduction' above.)

Preformed mediators – Preformed mediators are stored in secretory granules and released into the extracellular environment within seconds to minutes after mast cell activation. They are responsible for many of the acute signs and symptoms of mast cell-mediated allergic reactions. These mediators include histamine, neutral proteases, heparin proteoglycans, and some cytokines, such as tumor necrosis factor-alpha (TNF-alpha). (See 'Preformed mediators' above.)

Mediators formed upon activation – Following activation, mast cells use membrane phospholipids to synthesize additional eicosanoid mediators: Prostaglandins (PG), leukotrienes (LT), and platelet-activating factor (PAF). These mediators appear from 15 minutes to several hours after activation. Eicosanoids cause some of the symptoms of allergic reactions and are also important in cell recruitment and antigen presentation. (See 'Newly synthesized lipid mediators' above.)

Cytokines and chemokines – Mast cells produce multifunctional cytokines and chemokines that recruit and activate other cells to the inflammatory microenvironment. These include the T helper type 2 (Th2) cytokines, interleukin 4 (IL-4) and interleukin 5 (IL-5), which are thought to be important in the perpetuation of the allergic response, and several chemokines that recruit neutrophils and activate fibroblasts. (See 'Cytokines and chemokines' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

The UpToDate editorial staff acknowledges Michael Gurish, PhD, now deceased, who contributed to an earlier version of this topic review.

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Topic 3972 Version 16.0

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