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Biochemical Society Transactions Apr 2018Mast cells play pivotal roles in innate and adaptive immunities but are also culprits in allergy, autoimmunity, and cardiovascular diseases. Mast cells respond to... (Review)
Review
Mast cells play pivotal roles in innate and adaptive immunities but are also culprits in allergy, autoimmunity, and cardiovascular diseases. Mast cells respond to environmental changes by initiating regulated exocytosis/secretion of various biologically active compounds called mediators (e.g. proteases, amines, and cytokines). Many of these mediators are stored in granules/lysosomes and rely on intricate degranulation processes for release. Mast cell stabilizers (e.g. sodium cromoglicate), which prevent such degranulation processes, have therefore been clinically employed to treat asthma and allergic rhinitis. However, it has become increasingly clear that different mast cell diseases often involve multiple mediators that rely on overlapping but distinct mechanisms for release. This review illustrates existing evidence that highlights the diverse exocytic pathways in mast cells. We also discuss strategies to delineate these pathways so as to identify unique molecular components which could serve as new drug targets for more effective and specific treatments against mast cell-related diseases.
Topics: Amines; Animals; Cell Degranulation; Cell Fusion; Cytokines; Exocytosis; Humans; Lysosomes; Mast Cells; Peptide Hydrolases
PubMed: 29472369
DOI: 10.1042/BST20170450 -
Advances in Experimental Medicine and... 2011Proteases are the most abundant class of proteins produced by mast cells. Many of these are stored in membrane-enclosed intracellular granules until liberated by... (Review)
Review
Proteases are the most abundant class of proteins produced by mast cells. Many of these are stored in membrane-enclosed intracellular granules until liberated by degranulating stimuli, which include cross-linking of high affinity IgE receptor F(c)εRI by IgE bound to multivalent allergen. Understanding and separating the functions of the proteases is important because expression differs among mast cells in different tissue locations. Differences between laboratory animals and humans in protease expression also influence the degree of confidence with which results obtained in animal models of mast cell function can be extrapolated to humans. The inflammatory potential of mast cell proteases was the first aspect of their biology to be explored and has received the most attention, in part because some of them, notably tryptases and chymases, are biomarkers of local and systemic mast cell degranulation and anaphylaxis. Although some of the proteases indeed augment allergic inflammation and are potential targets for inhibition to treat asthma and related allergic disorders, they are protective and even anti-inflammatory in some settings. For example, mast cell tryptases may protect from serious bacterial lung infections and may limit the "rubor" component of inflammation caused by vasodilating neuropeptides in the skin. Chymases help to maintain intestinal barrier function and to expel parasitic worms and may support blood pressure during anaphylaxis by generating angiotensin II. In other life-or-death examples, carboxypeptidase A3 and other mast cell peptidases limit systemic toxicity of endogenous peptideslike endothelin and neurotensin during septic peritonitis and inactivate venom-associated peptides. On the other hand, mast cell peptidase-mediated destruction of protective cytokines, like IL-6, can enhance mortality from sepsis. Peptidases released from mast cells also influence nonmast cell proteases, such as by activating matrix metalloproteinase cascades, which are important in responses to infection and resolution of tissue injury. Overall, mast cell proteases have a variety of roles, inflammatory and anti-inflammatory, protective and deleterious, in keeping with the increasingly well-appreciated contributions of mast cells in allergy, tissue homeostasis and innate immunity.
Topics: Animals; Humans; Inflammation Mediators; Mast Cells; Peptide Hydrolases
PubMed: 21713659
DOI: 10.1007/978-1-4419-9533-9_12 -
European Journal of Pharmacology May 2016Mast cells are rich in proteases, which are the major proteins of intracellular granules and are released with histamine and heparin by activated cells. Most of these... (Review)
Review
Mast cells are rich in proteases, which are the major proteins of intracellular granules and are released with histamine and heparin by activated cells. Most of these proteases are active in the granule as well as outside of the mast cell when secreted, and can cleave targets near degranulating mast cells and in adjoining tissue compartments. Some proteases released from mast cells reach the bloodstream and may have far-reaching actions. In terms of relative amounts, the major mast cell proteases include the tryptases, chymases, cathepsin G, carboxypeptidase A3, dipeptidylpeptidase I/cathepsin C, and cathepsins L and S. Some mast cells also produce granzyme B, plasminogen activators, and matrix metalloproteinases. Tryptases and chymases are almost entirely mast cell-specific, whereas other proteases, such as cathepsins G, C, and L are expressed by a variety of inflammatory cells. Carboxypeptidase A3 expression is a property shared by basophils and mast cells. Other proteases, such as mastins, are largely basophil-specific, although human basophils are protease-deficient compared with their murine counterparts. The major classes of mast cell proteases have been targeted for development of therapeutic inhibitors. Also, a human β-tryptase has been proposed as a potential drug itself, to inactivate of snake venins. Diseases linked to mast cell proteases include allergic diseases, such as asthma, eczema, and anaphylaxis, but also include non-allergic diseases such as inflammatory bowel disease, autoimmune arthritis, atherosclerosis, aortic aneurysms, hypertension, myocardial infarction, heart failure, pulmonary hypertension and scarring diseases of lungs and other organs. In some cases, studies performed in mouse models suggest protective or homeostatic roles for specific proteases (or groups of proteases) in infections by bacteria, worms and other parasites, and even in allergic inflammation. At the same time, a clearer picture has emerged of differences in the properties and patterns of expression of proteases expressed in human mast cell subsets, and in humans versus other mammals. These considerations are influencing prioritization of specific protease targets for therapeutic inhibition, as well as options of pre-clinical models, disease indications, and choice of topical versus systemic routes of inhibitor administration.
Topics: Animals; Humans; Mast Cells; Molecular Targeted Therapy; Peptide Hydrolases
PubMed: 25958181
DOI: 10.1016/j.ejphar.2015.04.045 -
European Journal of Pharmacology May 2016Mast cells play crucial roles in both innate and adaptive arms of the immune system. Along with basophils, mast cells are essential effector cells for allergic... (Review)
Review
Mast cells play crucial roles in both innate and adaptive arms of the immune system. Along with basophils, mast cells are essential effector cells for allergic inflammation that causes asthma, allergic rhinitis, food allergy and atopic dermatitis. Mast cells are usually increased in inflammatory sites of allergy and, upon activation, release various chemical, lipid, peptide and protein mediators of allergic reactions. Since antigen/immunoglobulin E (IgE)-mediated activation of these cells is a central event to trigger allergic reactions, innumerable studies have been conducted on how these cells are activated through cross-linking of the high-affinity IgE receptor (FcεRI). Development of mature mast cells from their progenitor cells is under the influence of several growth factors, of which the stem cell factor (SCF) seems to be the most important. Therefore, how SCF induces mast cell development and activation via its receptor, KIT, has been studied extensively, including a cross-talk between KIT and FcεRI signaling pathways. Although our understanding of the signaling mechanisms of the FcεRI and KIT pathways is far from complete, pharmaceutical applications of the knowledge about these pathways are underway. This review will focus on recent progresses in FcεRI and KIT signaling and chemotaxis.
Topics: Animals; Chemotaxis; Humans; Mast Cells; Signal Transduction
PubMed: 25941081
DOI: 10.1016/j.ejphar.2015.02.057 -
Frontiers in Immunology 2021Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and... (Review)
Review
Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.
Topics: Animals; Calcium Signaling; Cell Death; Cell Degranulation; Cell Membrane; Cellular Microenvironment; Cholesterol; Cytokines; Cytotoxins; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Host-Pathogen Interactions; Humans; Inflammation Mediators; Mast Cells
PubMed: 34248949
DOI: 10.3389/fimmu.2021.670205 -
Blood Cells, Molecules & Diseases 2008Unregulated activation of mast cells can contribute to the pathogenesis of inflammatory and allergic diseases, including asthma, rheumatoid arthritis, inflammatory bowel... (Review)
Review
Unregulated activation of mast cells can contribute to the pathogenesis of inflammatory and allergic diseases, including asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. Absence of mast cells in animal models can lead to impairment in the innate immune response to parasites and bacterial infections. Aberrant clonal accumulation and proliferation of mast cells can result in a variety of diseases ranging from benign cutaneous mastocytosis to systemic mastocytosis or mast cell leukemia. Understanding mast cell differentiation provides important insights into mechanisms of lineage selection during hematopoiesis and can provide targets for new drug development to treat mast cell disorders. In this review, we discuss controversies related to development, sites of origin, and the transcriptional program of mast cells.
Topics: Animals; GATA1 Transcription Factor; Gene Regulatory Networks; Humans; Mast Cells; Protein Isoforms; Transcription Factors
PubMed: 18406636
DOI: 10.1016/j.bcmd.2008.02.005 -
Journal of Immunology (Baltimore, Md. :... Dec 2021Mast cells are important effector cells in the immune system and undergo activation (i.e., degranulation) by two major mechanisms: IgE-mediated and non-IgE-mediated...
Mast cells are important effector cells in the immune system and undergo activation (i.e., degranulation) by two major mechanisms: IgE-mediated and non-IgE-mediated mechanisms. Although IgE-mediated degranulation is well researched, the cellular mechanisms of non-IgE-mediated mast cell activation are poorly understood despite the potential to induce similar pathophysiological effects. To better understand non-IgE mast cell degranulation, we characterized and compared cellular metabolic shifts across several mechanisms of degranulation (allergen-induced [IgE-mediated], 20 nm of silver nanoparticle-mediated [non-IgE], and compound 48/80-mediated [non-IgE]) in murine bone marrow-derived mast cells. All treatments differentially impacted mitochondrial activity and glucose uptake, suggesting diverging metabolic pathways between IgE- and non-IgE-mediated degranulation. Non-IgE treatments depleted mast cells' glycolytic reserve, and compound 48/80 further inhibited the ability to maximize mitochondrial respiration. This cellular reprogramming may be indicative of a stress response with non-IgE treatments. Neither of these outcomes occurred with IgE-mediated degranulation, hinting at a separate programmed response. Fuel flexibility between the three primary mitochondrial nutrient sources was also eliminated in activated cells and this was most significant in non-IgE-mediated degranulation. Lastly, metabolomics analysis of bone marrow-derived mast cells following degranulation was used to compare general metabolite profiles related to energetic pathways. IgE-mediated degranulation upregulated metabolite concentrations for the TCA cycle and glycolysis compared with other treatments. In conclusion, mast cell metabolism varies significantly between IgE- and non-IgE-mediated degranulation suggesting novel cell regulatory mechanisms are potentially driving unexplored pathways of mast cell degranulation.
Topics: Animals; Cells, Cultured; Immunoglobulin E; Mast Cells; Mice; Mice, Inbred C57BL
PubMed: 34732470
DOI: 10.4049/jimmunol.2001278 -
BioMed Research International 2015An association between mast cells and tumor angiogenesis is known to exist, but the exact role that mast cells play in this process is still unclear. It is thought that... (Review)
Review
An association between mast cells and tumor angiogenesis is known to exist, but the exact role that mast cells play in this process is still unclear. It is thought that the mediators released by mast cells are important in neovascularization. However, it is not known how individual mediators are involved in this process. The major constituents of mast cell secretory granules are the mast cell specific proteases chymase, tryptase, and carboxypeptidase A3. Several previous studies aimed to understand the way in which specific mast cell granule constituents act to induce tumor angiogenesis. A body of evidence indicates that mast cell proteases are the pivotal players in inducing tumor angiogenesis. In this review, the likely mechanisms by which tryptase and chymase can act directly or indirectly to induce tumor angiogenesis are discussed. Finally, information presented here in this review indicates that mast cell proteases significantly influence angiogenesis thus affecting tumor growth and progression. This also suggests that these proteases could serve as novel therapeutic targets for the treatment of various types of cancer.
Topics: Chymases; Humans; Mast Cells; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Tryptases
PubMed: 26146612
DOI: 10.1155/2015/142359 -
Critical Reviews in Immunology 2011Mast cells are multifunctional cells that initiate not only IgE-dependent allergic diseases but also play a fundamental role in innate and adaptive immune responses to... (Review)
Review
Mast cells are multifunctional cells that initiate not only IgE-dependent allergic diseases but also play a fundamental role in innate and adaptive immune responses to microbial infection. They are also thought to play a role in angiogenesis, tissue remodeling, wound healing, and tumor repression or growth. The broad scope of these physiologic and pathologic roles illustrates the flexible nature of mast cells, which is enabled in part by their phenotypic adaptability to different tissue microenvironments and their ability to generate and release a diverse array of bioactive mediators in response to multiple types of cell-surface and cytosolic receptors. There is increasing evidence from studies in cell cultures that release of these mediators can be selectively modulated depending on the types or groups of receptors activated. The intent of this review is to foster interest in the interplay among mast cell receptors to help understand the underlying mechanisms for each of the immunological and non-immunological functions attributed to mast cells. The second intent of this review is to assess the pathophysiologic roles of mast cells and their products in health and disease. Although mast cells have a sufficient repertoire of bioactive mediators to mount effective innate and adaptive defense mechanisms against invading microorganisms, these same mediators can adversely affect surrounding tissues in the host, resulting in autoimmune disease as well as allergic disorders.
Topics: Animals; Humans; Ligands; Mast Cells; Phenotype; Receptors, G-Protein-Coupled; Receptors, Immunologic; Signal Transduction
PubMed: 22321108
DOI: 10.1615/critrevimmunol.v31.i6.30 -
Cells Mar 2020Mast cells have been associated with arteriogenesis and collateral formation. In advanced human atherosclerotic plaques, mast cells have been shown to colocalize with...
Mast cells have been associated with arteriogenesis and collateral formation. In advanced human atherosclerotic plaques, mast cells have been shown to colocalize with plaque neovessels, and mast cells have also been associated with tumor vascularization. Based on these associations, we hypothesize that mast cells promote angiogenesis during ischemia. In human ischemic muscle tissue from patients with end-stage peripheral artery disease, we observed activated mast cells, predominantly located around capillaries. Also, in mouse ischemic muscles, mast cells were detected during the revascularization process and interestingly, mast cell activation status was enhanced up to 10 days after ischemia induction. To determine whether mast cells contribute to both arteriogenesis and angiogenesis, mast cells were locally activated immediately upon hind limb ischemia in C57Bl/6 mice. At day 9, we observed a 3-fold increase in activated mast cell numbers in the inguinal lymph nodes. This was accompanied by an increase in the amount of Ly6C inflammatory monocytes. Interestingly, local mast cell activation increased blood flow through the hind limb (46% at day 9) compared to that in non-activated control mice. Histological analysis of the muscle tissue revealed that mast cell activation did not affect the number of collaterals, but increased the collateral diameter, as well as the number of CD31 capillaries. Together, these data illustrate that locally activated mast cell contribute to arteriogenesis and angiogenesis.
Topics: Animals; Disease Models, Animal; Humans; Immunity, Innate; Mast Cells; Mice; Neovascularization, Physiologic
PubMed: 32178480
DOI: 10.3390/cells9030701