What do mast cells produce

GRK2 is one of the members of this group that is known to desensitize H1R and limits its signaling , Endothelial cells and smooth muscle cells highly express H1R and this receptor facilitates histamine-mediated inflammatory and hypersensitivity responses , The clinical significance of mast cell-derived histamine in CVD is evident from the finding that coronary arteries of patients with ischemic heart disease contain more mast cells and histamine than normal vessels , and patients with variant angina have elevated levels of histamine in their coronary circulation Reports have suggested that histamine induces smooth muscle cell migration and proliferation , , and regulates intimal thickening model Histamine also increases endothelial cell responses to TLR2 and TLR4 ligands by increasing the expression of these two innate immune receptors , , Figure 2.

Scheme showing the synergistic activation of inflammatory response in endothelial cells by mast cell-derived histamine and bacterial products. A Histamine secreted by the mast cell stimulates H1R on endothelial cells. Therefore, it is unclear whether H1R signaling of histamine is proatherogenic or cardioprotective.

Some studies show that H1 antihistamines reduce atherogenesis in apoE-deficient mice , Raveendran et al. Increased atheroma formation and lesion area were noted in mice with low doses of cetirizine or fexofenadine. This was not associated with increased macrophage, mast cell, or T lymphocyte count. Reduction in the number of mast cells may be due to increased degranulation. However, high doses of cetirizine and fexofenadine did not increase atherosclerosis compared to the control. Ingestion of H1 antihistamines did not alter H1R expression in the plaque area as determined by immunofluorescence.

At high doses, the antihistamines may bind to other receptors, such as H4R, which may result in the different response seen than binding H1R. Therefore, antihistamines continue to show a mixed picture with respect to atherosclerosis It should be noted that the vasodilatory effects of histamine may promote lipid accumulation in the vessel wall. In summary, mast cells play a key role in regulation of normal physiological processes as well as in many pathophysiological settings.

Considerable progress has been made in our understanding of these immune cells in recent years. Additional efforts to define the complex interactions of mast cells will potentially lead to novel clinical approaches for many pathological conditions. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Mast cell function: a new vision of an old cell. J Histochem Cytochem 62 10 — Galli SJ, Tsai M.

Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity. Eur J Immunol 40 7 — Identification and characterization of undifferentiated mast cells in mouse bone marrow. Blood 11 —9. Mast cell biology in evolution. J Allergy Clin Immunol 6 —9. Mechanisms underlying the localisation of mast cells in tissues.

Trends Immunol 32 10 — Two types of human mast cells that have distinct neutral protease compositions. Schwartz LB. Methods Mol Biol — PubMed Abstract Google Scholar. Coordinated regulation of NK receptor expression in the maturing human immune system.

J Immunol 10 —9. Bradding P. Allergen immunotherapy and mast cells. Clin Exp Allergy 29 11 —8. New roles for mast cells in modulating allergic reactions and immunity against pathogens. Curr Opin Immunol 21 6 — Mast cells in the development of adaptive immune responses.

Nat Immunol 6 2 — On the mechanism of the copper-catalyzed cyclopropanation reaction. Chemistry 8 1 — Google Scholar. Siraganian RP. Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin Immunol 15 6 — Mast cell activation: a complex interplay of positive and negative signaling pathways.

Eur J Immunol 44 9 — Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol 9 11 — Roles of adaptor molecules in mast cell activation. Chem Immunol Allergy 87 — Phospholipase D1 regulates high-affinity IgE receptor-induced mast cell degranulation. Blood 13 —8. The transcription factor Zeb2 regulates signaling in mast cells.

J Immunol 12 — Shalit M, Levi-Schaffer F. Challenge of mast cells with increasing amounts of antigen induces desensitization. Clin Exp Allergy 25 9 — Norrby K. Mast cells and angiogenesis. APMIS 5 — Bulfone-Paus S, Bahri R. Mast cells as regulators of T cell responses. Front Immunol 6 The gut microbiota and inflammatory bowel disease. Curr Opin Rheumatol 27 4 — Marshall JS.

Mast-cell responses to pathogens. Nat Rev Immunol 4 10 — Mast cell functions in the innate skin immune system. Immunobiology 3—4 — Eur J Immunol 33 4 — Cutting edge: distinct toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells.

J Immunol 4 —9. Blood 3 — Activation of mast cells by double-stranded RNA: evidence for activation through toll-like receptor 3. J Allergy Clin Immunol 1 — Immunity 31 4 — Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 4 — IgE-mediated mast cell degranulation and recovery monitored by time-lapse photography.

Basu S, Fenton MJ. Toll-like receptors: function and roles in lung disease. Differential responses of mast cell toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest 10 —9. Active caspase-3 is stored within secretory compartments of viable mast cells. J Immunol 3 — Mast cell-derived proteases control allergic inflammation through cleavage of IgE. Nature —6. Blood 24 —7. J Biol Chem 16 —7. Malaviya R, Abraham SN. Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis.

J Leukoc Biol 67 6 —6. Boyce JA. Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulation. Immunol Rev — Mast cells mediate the microvascular inflammatory response to systemic hypoxia. J Appl Physiol 94 1 — Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats. J Appl Physiol 89 4 —8. Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia.

Exp Physiol 91 5 — Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules. J Appl Physiol 95 6 — Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia. Mast cell degranulation promotes ischemia-reperfusion injury in rat liver.

J Surg Res 1 —8. The role of mast cells in ischemia and reperfusion injury. Inflamm Res 63 11 — A blockade of complement activation prevents rapid intestinal ischaemia-reperfusion injury by modulating mucosal mast cell degranulation in rats. Clin Exp Immunol 3 — Reactive oxygen species and nitric oxide in myocardial ischemia and reperfusion. G protein-coupled receptors and the modification of FcepsilonRI-mediated mast cell activation.

Immunol Lett 2 — Receptors and signaling mechanisms required for prostaglandin E2-mediated regulation of mast cell degranulation and IL-6 production. J Immunol 8 — Mast cells: a unique source of renin. J Clin Invest 4 — Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells. Circulation 8 — Hartman J, Frishman WH. Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy.

Cardiol Rev 22 3 — Immune mechanisms in atherosclerosis. Arteriosclerosis 9 5 — Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med 5 — Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 91 4 — Angiotensin induces inflammatory activation of human vascular smooth muscle cells.

Arterioscler Thromb Vasc Biol 19 7 —9. Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation. Circulation 18 —9. Kovanen PT. Role of mast cells in atherosclerosis. Chem Immunol 62 — Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice.

Circulation 19 — Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation 99 3 —9. Innate immune system cells in atherosclerosis. Arch Med Res 45 1 :1— J Clin Invest 9 — Mast cells induce vascular smooth muscle cell apoptosis via a toll-like receptor 4 activation pathway. Arterioscler Thromb Vasc Biol 32 8 —9.

PLoS One 8 4 :e Tryptase promotes human monocyte-derived macrophage foam cell formation by suppressing LXRalpha activation. Biochim Biophys Acta 5 — Cytokine production by mast cells and basophils. Curr Opin Immunol 3 6 — Mast cells: important players in the orchestrated pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 31 4 — Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J Clin Invest 11 — Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm.

Circ Res 11 — Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study. Lancet — Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors. J Vasc Surg 33 5 — Perforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm.

Am J Pathol 2 — Mast cells as effectors in atherosclerosis. Arterioscler Thromb Vasc Biol 35 2 — Neovascularization and coronary atherosclerotic plaque: cinematographic localization and quantitative histologic analysis. Hum Pathol 18 10 — Mast cells accompany microvessels in human coronary atheromas: implications for intimal neovascularization and hemorrhage. Atherosclerosis 1—2 — Mast cells promote atherosclerosis by releasing proinflammatory cytokines.

Nat Med 13 6 — Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions. Arterioscler Thromb Vasc Biol 23 2 — Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-kappaB-mediated survival signaling.

Exp Cell Res 8 — Activated mast cells induce endothelial cell apoptosis by a combined action of chymase and tumor necrosis factor-alpha.

Arterioscler Thromb Vasc Biol 28 2 — Low-density-lipoprotein binding by mast-cell granules. Demonstration of binding of apolipoprotein B to heparin proteoglycan of exocytosed granules. Mast cells are allergy cells responsible for immediate allergic reactions. In allergic reactions, this release occurs when the allergy antibody IgE , which is present on the mast cell surfaces, binds to proteins that cause allergies, called allergens.

This triggering is called activation, and the release of these mediators is called degranulation. Some of these mediators are stored in granules in the mast cells and are released quickly and others are made slowly only after the cell has been triggered. Mast cells can also be activated by other substances, such as medications, infections, insect or reptile venoms.

Sometimes mast cells become defective and release mediators because of abnormal internal signals. Certain mutations in mast cells can produce populations of identical mast cells — called clones — that overproduce and spontaneously release mediators. These abnormal cells can grow uncontrollably and are unusually sensitive to activation in a condition called mastocytosis.

MCAS is a condition in which the patient experiences repeated episodes of the symptoms of anaphylaxis — allergic symptoms such as hives, swelling, low blood pressure, difficulty breathing and severe diarrhea. High levels of mast cell mediators are released during those episodes.

The episodes respond to treatment with inhibitors or blockers of mast cell mediators. Evaluation for MCAS starts with determining whether the symptoms occur in separate attacks and are typical symptoms of an anaphylactic reaction without a clear cause. Mast cell mediators increase during the episode. Those mediators should be measured during acute episodes and at baseline looking for elevations during symptoms. Mast cells in plaque are located near microvessels 77 , When mast cells degranulate, they release histamine and matrix degrading proteases, which can cause microvessel leakiness and rupture leading to intraplaque hemorrhage.

Mast cell activation during atherosclerosis was shown to increase the size of the plaque in the brachiocephalic artery of apoE-deficient mice This response was prevented by administration of cromolyn.

Another study showed that mast cell deficiency inhibited development of atherosclerotic plaque in LDL receptor-deficient mice Mast cells can be seen as effector cells to induce plaque formation and progression. Overexpression of mast cell tryptase in mice had a greater risk of intraplaque hemorrhage Additionally, a patient cohort study found that serum chymase levels were higher in patients with coronary heart disease.

Chymase can modify HDL, affect cholesterol efflux ability, and also enhance the production of Angiotensin II, which is a proatherogenic factor.

Chymase also induces apoptosis of vascular smooth muscle cells and endothelial cells 80 — Activation of mast cells promotes enhanced lipid uptake by macrophages. Heparin-bound LDL is phagocytosed by macrophages to form foam cells 83 , Mast cell activation during plaque development leads to progression and increased leukocyte infiltration and lipid accumulation.

The resulting leakiness of microvessels in advanced unstable lesions can lead to hemorrhage of the plaque or rupture of the fibrous cap.

This can then result in thrombosis and acute cardiovascular events. Mast cell activation in the plaque can be through IgE-dependent or IgE-independent pathways.

IgE levels are high in patients with angina pectoris However, another study showed that plasma IgE levels did not correlate with disease progression or mast cell numbers in Western populations This suggests that mast cell activation in the progression of atherosclerotic plaques may be initiated by another mechanism, such as plaque lipids, which can activate mast cells in the vessel wall.

Another mechanism of activation is through C5a activation via C5aR on mast cells. Activated complement is found within the plaque. Activation of mast cells with C5a resulted in an increase in vein graft atherosclerosis, which was inhibited by cromolyn Activation of mast cells can be accomplished via neuropeptides, such as substance P, as mast cells are in close proximity to nerve fibers.

Use of mast cell stabilizers for halting plaque progression would be a reasonable treatment option Mast cells are increased in coronary arteries during spasm and in the rupture prone shoulders of coronary atheromas Risk factors, such as oxidized LDL, reactive oxygen species, complement 5a, substance P, endothelin-1, and thrombin can activate mast cells 87 — Mast cells synthesize and secrete histamine, proteases, prostaglandin D2, leukotrienes, heparin, and a variety of cytokines, many of which are implicated in CVD 36 , 93 — Furthermore, mast cells enhance endothelial inflammatory responses through upregulation of innate immune mechanisms , The clinical significance of mast cells in CVD is evident from their increased presence in the adventitia of coronary arteries of patients with atherosclerosis 98 , — An increase in the number of mast cells is also found to be associated with thrombus formation Endothelial cells can endocytose MCG in vitro , and in vivo MCGs are also involved in the induction of human microvascular endothelial cell proliferation , LDL uptake by macrophages, and foam cell formation , Although these findings suggest an important role for mast cells in CVD, the mechanism by which mast cell products promote atherogenesis and CVD is not well understood.

Histamine is a major secretory product of the mast cell and is recognized for its role in the regulation of vasodilation and bronchoconstriction , Histamine also regulates functions of monocytes and macrophages , , eosinophils , , T cells , neutrophils, and endothelial cells , GRKs are a group of seven mammalian serine and threonine protein kinases GRK2 is one of the members of this group that is known to desensitize H1R and limits its signaling , Endothelial cells and smooth muscle cells highly express H1R and this receptor facilitates histamine-mediated inflammatory and hypersensitivity responses , The clinical significance of mast cell-derived histamine in CVD is evident from the finding that coronary arteries of patients with ischemic heart disease contain more mast cells and histamine than normal vessels , and patients with variant angina have elevated levels of histamine in their coronary circulation Reports have suggested that histamine induces smooth muscle cell migration and proliferation , , and regulates intimal thickening model Histamine also increases endothelial cell responses to TLR2 and TLR4 ligands by increasing the expression of these two innate immune receptors , , Scheme showing the synergistic activation of inflammatory response in endothelial cells by mast cell-derived histamine and bacterial products.

A Histamine secreted by the mast cell stimulates H1R on endothelial cells. Therefore, it is unclear whether H1R signaling of histamine is proatherogenic or cardioprotective. Some studies show that H1 antihistamines reduce atherogenesis in apoE-deficient mice , Raveendran et al. Increased atheroma formation and lesion area were noted in mice with low doses of cetirizine or fexofenadine.

This was not associated with increased macrophage, mast cell, or T lymphocyte count. Reduction in the number of mast cells may be due to increased degranulation. However, high doses of cetirizine and fexofenadine did not increase atherosclerosis compared to the control. Ingestion of H1 antihistamines did not alter H1R expression in the plaque area as determined by immunofluorescence. At high doses, the antihistamines may bind to other receptors, such as H4R, which may result in the different response seen than binding H1R.

Therefore, antihistamines continue to show a mixed picture with respect to atherosclerosis It should be noted that the vasodilatory effects of histamine may promote lipid accumulation in the vessel wall. In summary, mast cells play a key role in regulation of normal physiological processes as well as in many pathophysiological settings. Considerable progress has been made in our understanding of these immune cells in recent years. Additional efforts to define the complex interactions of mast cells will potentially lead to novel clinical approaches for many pathological conditions.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Immunol v. Front Immunol. Published online Jan 6.

Melissa Krystel-Whittemore , 1 Kottarappat N. Dileepan , 2 and John G. Kottarappat N. John G. Author information Article notes Copyright and License information Disclaimer. Wood, ude. Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology. Received Aug 17; Accepted Nov The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Mast cells are immune cells of the myeloid lineage and are present in connective tissues throughout the body.

Keywords: mast cell, immune system, inflammatory mediators, systemic hypoxia, atherogenesis. Introduction Mast cells are important cells of the immune system and are of the hematopoietic lineage. Location of Mast Cells Mast cells are found in mucosal and epithelial tissues throughout the body.

Physiological Roles of Mast Cells Mast cells are involved in the regulation of variety of physiological functions, including vasodilation, angiogenesis, bacterial, and parasite elimination. Angiogenesis Mast cells are involved with enhancing angiogenesis Homeostasis Mast cells contribute to homeostasis in the immune system. Innate and Adaptive Immunity Mast cells play an important role in innate and adaptive immunity. Activation and Mediator Release Mast cells upon activation release preformed and newly synthesized mediators in a phasic fashion.

Open in a separate window. Figure 1. Major substances released by activated mast cells. Microvascular Inflammation in Systemic Hypoxia Mast cells mediate microvascular inflammatory response to systemic hypoxia caused by a reduction in the level of inspired oxygen Atherosclerosis Atherosclerosis is an inflammatory process that involves innate and adaptive immunity Figure 2.

Conclusion In summary, mast cells play a key role in regulation of normal physiological processes as well as in many pathophysiological settings. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References 1. Mast cell function: a new vision of an old cell. J Histochem Cytochem 62 10 — Galli SJ, Tsai M.

Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity. Eur J Immunol 40 7 — Identification and characterization of undifferentiated mast cells in mouse bone marrow.

Blood 11 —9. Mast cell biology in evolution. J Allergy Clin Immunol 6 —9. Mechanisms underlying the localisation of mast cells in tissues. Trends Immunol 32 10 — Two types of human mast cells that have distinct neutral protease compositions. Schwartz LB.

Methods Mol Biol — Coordinated regulation of NK receptor expression in the maturing human immune system. J Immunol 10 —9. Bradding P. Allergen immunotherapy and mast cells.

Clin Exp Allergy 29 11 —8. New roles for mast cells in modulating allergic reactions and immunity against pathogens. Curr Opin Immunol 21 6 — Mast cells in the development of adaptive immune responses. Nat Immunol 6 2 — On the mechanism of the copper-catalyzed cyclopropanation reaction. Chemistry 8 1 — Siraganian RP. Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin Immunol 15 6 — Mast cell activation: a complex interplay of positive and negative signaling pathways.

Eur J Immunol 44 9 — Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol 9 11 — Roles of adaptor molecules in mast cell activation. Chem Immunol Allergy 87 — Phospholipase D1 regulates high-affinity IgE receptor-induced mast cell degranulation.

Blood 13 —8. The transcription factor Zeb2 regulates signaling in mast cells. J Immunol 12 — Shalit M, Levi-Schaffer F. Challenge of mast cells with increasing amounts of antigen induces desensitization. Clin Exp Allergy 25 9 — Norrby K. Mast cells and angiogenesis. APMIS 5 — Bulfone-Paus S, Bahri R. Mast cells as regulators of T cell responses. Front Immunol 6 The gut microbiota and inflammatory bowel disease. Curr Opin Rheumatol 27 4 — Marshall JS. Mast-cell responses to pathogens.

Nat Rev Immunol 4 10 — Mast cell functions in the innate skin immune system. Immunobiology 3—4 — Eur J Immunol 33 4 — Cutting edge: distinct toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells.

J Immunol 4 —9. Blood 3 — Activation of mast cells by double-stranded RNA: evidence for activation through toll-like receptor 3. J Allergy Clin Immunol 1 — Immunity 31 4 — Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 4 — IgE-mediated mast cell degranulation and recovery monitored by time-lapse photography.

Basu S, Fenton MJ. Toll-like receptors: function and roles in lung disease. Differential responses of mast cell toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest 10 —9. Active caspase-3 is stored within secretory compartments of viable mast cells. J Immunol 3 — Mast cell-derived proteases control allergic inflammation through cleavage of IgE. Nature —6. Blood 24 —7. J Biol Chem 16 —7. Malaviya R, Abraham SN. Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis.

J Leukoc Biol 67 6 —6. Boyce JA. Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulation. Immunol Rev — Mast cells mediate the microvascular inflammatory response to systemic hypoxia. J Appl Physiol 94 1 — Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats. J Appl Physiol 89 4 —8. Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia.

Exp Physiol 91 5 — Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules. J Appl Physiol 95 6 — Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia. Mast cell degranulation promotes ischemia-reperfusion injury in rat liver.

J Surg Res 1 —8. The role of mast cells in ischemia and reperfusion injury. Inflamm Res 63 11 — A blockade of complement activation prevents rapid intestinal ischaemia-reperfusion injury by modulating mucosal mast cell degranulation in rats. Clin Exp Immunol 3 — Reactive oxygen species and nitric oxide in myocardial ischemia and reperfusion. G protein-coupled receptors and the modification of FcepsilonRI-mediated mast cell activation.

Immunol Lett 2 — Receptors and signaling mechanisms required for prostaglandin E2-mediated regulation of mast cell degranulation and IL-6 production.

J Immunol 8 — Mast cells: a unique source of renin. J Clin Invest 4 —