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==Function== [[Image:Mast cells.jpg|thumb|right|220px|The role of mast cells in the development of allergy.]] Mast cells play a key role in the inflammatory process. When activated, a mast cell can either selectively release ('''piecemeal degranulation''') or rapidly release ('''anaphylactic degranulation''') "mediators", or compounds that induce inflammation, from storage [[Granule (cell biology)|granules]] into the local microenvironment.<ref name="Mast cell function" /><ref name="Mast cell mediators - eoxins" /> Mast cells can be stimulated to [[Degranulation|degranulate]] by [[allergen]]s through [[cross-link]]ing with [[immunoglobulin E]] receptors (e.g., [[FcεRI]]), physical injury through [[pattern recognition receptor]]s for [[damage-associated molecular patterns]] (DAMPs), [[pathogen|microbial pathogen]]s through pattern recognition receptors for [[pathogen-associated molecular patterns]] (PAMPs), and various compounds through their associated [[G-protein coupled receptor]]s (e.g., morphine through [[opioid receptor]]s) or [[ligand-gated ion channel]]s.<ref name="Mast cell function" /><ref name="Mast cell mediators - eoxins" /> [[Complement system|Complement proteins]] can activate membrane receptors on mast cells to exert various functions as well.<ref name=Prussin/> Mast cells express a high-affinity receptor ([[FcεRI]]) for the Fc region of IgE, the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is in essence irreversible. As a result, mast cells are coated with IgE, which is produced by [[plasma cell]]s (the antibody-producing cells of the immune system). IgE antibodies are typically specific to one particular [[antigen]]. In allergic reactions, mast cells remain inactive until an [[allergen]] binds to IgE already coated upon the cell. Other membrane activation events can either prime mast cells for subsequent degranulation or act in synergy with FcεRI signal transduction.<ref name="pmid18463655">{{cite journal |vauthors=Pulendran B, Ono SJ | title = A shot in the arm for mast cells | journal = Nat. Med. | volume = 14 | issue = 5 | pages = 489–90 |date=May 2008 | pmid = 18463655 | doi = 10.1038/nm0508-489 | s2cid = 205378470 | doi-access = free }}</ref> In general, allergens are [[protein]]s or [[polysaccharide]]s. The allergen binds to the antigen-binding sites, which are situated on the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of two or more IgE molecules (cross-linking) is required to activate the mast cell. The clustering of the intracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgE molecules, causes a complex sequence of reactions inside the mast cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against parasites and bacteria.<ref>{{cite journal |vauthors=Lee J, Veatch SL, Baird B, Holowka D |title=Molecular mechanisms of spontaneous and directed mast cell motility |journal=J. Leukoc. Biol. |volume=92 |issue=5 |pages=1029–41 |year=2012 |pmid=22859829 |pmc=3476239 |doi=10.1189/jlb.0212091 }}</ref> Mast cells (MCs) have been shown to release their nuclear DNA and subsequently form mast cell extracellular traps (MCETs) comparable to neutrophil extracellular traps, which are able to entrap and kill various microbes.<ref>{{Cite journal |last1=Möllerherm |first1=Helene |last2=von Köckritz-Blickwede |first2=Maren |last3=Branitzki-Heinemann |first3=Katja |date=2016-07-18 |title=Antimicrobial Activity of Mast Cells: Role and Relevance of Extracellular DNA Traps |journal=Frontiers in Immunology |language=en |volume=7 |page=265 |doi=10.3389/fimmu.2016.00265 |doi-access=free |pmid=27486458 |pmc=4947581 |issn=1664-3224 }}</ref> ===Mast cell mediators=== <!--Several pages link to this heading; please do not change the section header without adding "{{Anchor|Mast cell mediators}}" between the "===". Without this anchor, the change will result in broken section links. --> A unique, stimulus-specific set of mast cell mediators is released through degranulation following the activation of [[cell surface receptor]]s on mast cells.<ref name="Mast cell mediators - eoxins" /> Examples of mediators that are released into the extracellular environment during mast cell degranulation include:<ref name=Prussin/><ref name="Mast cell mediators - eoxins" /><ref name="pmid23600539">{{cite journal | vauthors = Ashmole I, Bradding P | title = Ion channels regulating mast cell biology | journal = Clin. Exp. Allergy | volume = 43 | issue = 5 | pages = 491–502 | date = May 2013 | pmid = 23600539 | doi = 10.1111/cea.12043 | s2cid = 1127584 | quote = P2X receptors are ligand-gated non-selective cation channels that are activated by extracellular ATP. ... Increased local ATP concentrations are likely to be present around mast cells in inflamed tissues due to its release through cell injury or death and platelet activation [40]. Furthermore, mast cells themselves store ATP within secretory granules, which is released upon activation [41]. There is therefore the potential for significant Ca2+ influx into mast cells through P2X receptors. Members of the P2X family differ in both the ATP concentration they require for activation and the degree to which they desensitise following agonist activation [37, 38]. This opens up the possibility that by expressing a number of different P2X receptors mast cells may be able to tailor their response to ATP in a concentration dependent manner [37].}}</ref> * [[serine protease]]s, such as [[tryptase]] and [[chymase]] * [[histamine]] (2–5 [[picogram]]s per mast cell) * [[serotonin]] * [[proteoglycan]]s, mainly [[heparin]] (active as [[anticoagulant]]) and some [[chondroitin sulfate proteoglycan]]s * [[adenosine triphosphate]] (ATP) * [[lysosomal enzymes]] ** [[Hexosaminidase|β-hexosaminidase]] ** [[β-glucuronidase]] ** [[arylsulfatase]]s * newly formed lipid mediators ([[eicosanoid]]s): ** [[thromboxane]] ** [[prostaglandin D2]] ** [[leukotriene C4]] ** [[platelet-activating factor]] * [[cytokine]]s ** [[TNF-α]] ** [[basic fibroblast growth factor]] ** [[interleukin-4]] ** [[stem cell factor]] ** [[chemokine]]s, such as [[eosinophil chemotactic factor]] * [[reactive oxygen species]] [[Image:Histamine.svg|thumb|right|250px|Structure of histamine]] Histamine dilates post-capillary venules, [[endothelial activation|activates the endothelium]], and increases blood vessel permeability. This leads to local [[edema]] (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. It also depolarizes [[nerve ending]]s (leading to [[itching]] or [[pain]]). Cutaneous signs of histamine release are the "flare and [[wheal response|wheal]]"-reaction. The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen.<ref name=Prussin/> The other physiologic activities of mast cells are much less-understood. Several lines of evidence suggest that mast cells may have a fairly fundamental role in [[innate immunity]]: They are capable of elaborating a vast array of important cytokines and other inflammatory mediators such as TNF-α; they express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of pathogens; and mice without mast cells seem to be much more susceptible to a variety of infections.{{Citation needed|date=June 2007}} Mast cell granules carry a variety of bioactive chemicals. These granules have been found to be transferred to adjacent cells of the immune system and [[neurons]] in a process of transgranulation via mast cell [[pseudopodia]].<ref name="pmid16262662">{{cite journal |vauthors=Wilhelm M, Silver R, Silverman AJ |title=Central nervous system neurons acquire mast cell products via transgranulation |journal=The European Journal of Neuroscience |volume=22 |issue=9 |pages=2238–48 |date=November 2005 |pmid=16262662 |pmc=3281766 |doi=10.1111/j.1460-9568.2005.04429.x}}</ref> ===In the nervous system=== Unlike other [[hematopoietic cell]]s of the [[immune system]], mast cells naturally occur in the [[human brain]] where they interact with the [[neuroimmune system]].<ref name="Mast cell neuroimmmune system">{{cite journal | vauthors = Polyzoidis S, Koletsa T, Panagiotidou S, Ashkan K, Theoharides TC | title = Mast cells in meningiomas and brain inflammation | journal = J Neuroinflammation | volume = 12 | issue = 1 | pages = 170 | year = 2015 | pmid = 26377554 | pmc = 4573939 | doi = 10.1186/s12974-015-0388-3 | quote = MCs originate from a bone marrow progenitor and subsequently develop different phenotype characteristics locally in tissues. Their range of functions is wide and includes participation in allergic reactions, innate and adaptive immunity, inflammation, and autoimmunity [34]. In the human brain, MCs can be located in various areas, such as the pituitary stalk, the pineal gland, the area postrema, the choroid plexus, thalamus, hypothalamus, and the median eminence [35]. In the meninges, they are found within the dural layer in association with vessels and terminals of meningeal nociceptors [36]. MCs have a distinct feature compared to other hematopoietic cells in that they reside in the brain [37]. MCs contain numerous granules and secrete an abundance of prestored mediators such as corticotropin-releasing hormone (CRH), neurotensin (NT), substance P (SP), tryptase, chymase, vasoactive intestinal peptide (VIP), vascular endothelial growth factor (VEGF), TNF, prostaglandins, leukotrienes, and varieties of chemokines and cytokines some of which are known to disrupt the integrity of the blood-brain barrier (BBB) [38–40].<br /><br />[The] key role of MCs in inflammation [34] and in the disruption of the BBB [41–43] suggests areas of importance for novel therapy research. Increasing evidence also indicates that MCs participate in neuroinflammation directly [44–46] and through microglia stimulation [47], contributing to the pathogenesis of such conditions such as headaches, [48] autism [49], and chronic fatigue syndrome [50]. In fact, a recent review indicated that peripheral inflammatory stimuli can cause microglia activation [51], thus possibly involving MCs outside the brain. | doi-access = free }}</ref> In the brain, mast cells are located in a number of structures that mediate visceral sensory (e.g. pain) or [[neuroendocrine]] functions or that are located along the [[blood–cerebrospinal fluid barrier]], including the [[pituitary stalk]], [[pineal gland]], [[thalamus]], and [[hypothalamus]], [[area postrema]], [[choroid plexus]], and in the dural layer of the [[meninges]] near meningeal [[nociceptor]]s.<ref name="Mast cell neuroimmmune system" /> Mast cells serve the same general functions in the body and central nervous system, such as effecting or regulating allergic responses, innate and adaptive immunity, [[autoimmunity]], and inflammation.<ref name="Mast cell neuroimmmune system" /><ref name="pmid32423330">{{cite journal | vauthors = Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J | title = Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update | journal = J Cereb Blood Flow Metab | date = May 2020 | volume = 40 | issue = 9 | pages = 1752–1768 | pmid = 32423330 | doi = 10.1177/0271678X20923551 | pmc = 7446569 }}</ref> Across systems, mast cells serve as the main [[effector cell]] through which pathogens can affect the [[gut–brain axis]].<ref name="pmid24833851" /><ref name="Microbiome-CNS-ENS" /> ===In the gut=== In the gastrointestinal tract, mucosal mast cells are located in close proximity to sensory nerve fibres, which communicate bidirectionally.<ref name="FGID mast cell" /><ref name="pmid24833851">{{cite journal | vauthors = Budzyński J, Kłopocka M | title = Brain-gut axis in the pathogenesis of Helicobacter pylori infection | journal = World J. Gastroenterol. | volume = 20 | issue = 18 | pages = 5212–25 | year = 2014 | pmid = 24833851 | pmc = 4017036 | doi = 10.3748/wjg.v20.i18.5212 | quote = In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector | doi-access = free }}</ref><ref name="Microbiome-CNS-ENS">{{cite journal | vauthors = Carabotti M, Scirocco A, Maselli MA, Severi C | title = The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems | journal = Ann Gastroenterol | volume = 28 | issue = 2 | pages = 203–209 | year = 2015 | pmid = 25830558 | pmc = 4367209 }}</ref> When these mast cells initially degranulate, they release mediators (e.g., histamine, tryptase, and serotonin) which activate, sensitize, and [[Downregulation and upregulation|upregulate membrane expression]] of [[nociceptor]]s (i.e., [[TRPV1]]) on visceral [[afferent neuron]]s via their receptors (respectively, [[HRH1]], [[HRH2]], [[HRH3]], [[Protease-activated receptor 2|PAR2]], [[5-HT3]]);<ref name="FGID mast cell" /> in turn, neurogenic inflammation, [[visceral hypersensitivity]], and [[Gastrointestinal physiology#Motility|intestinal dysmotility]] (i.e., impaired [[peristalsis]]) result.<ref name="FGID mast cell" /> Neuronal activation induces neuropeptide ([[substance P]] and [[calcitonin gene-related peptide]]) signaling to mast cells where they bind to their associated [[G-protein coupled receptor|receptor]]s and trigger degranulation of a distinct set of mediators ([[hexosaminidase|β-Hexosaminidase]], [[cytokines]], [[chemokines]], [[PGD2]], [[leukotriene]]s, and [[eoxin]]s<!--"15-LO" in the lipid body biogenesis diagram is the synthesizing enzyme for eoxins-->).<ref name="FGID mast cell">{{cite journal | vauthors = Wouters MM, Vicario M, Santos J | title = The role of mast cells in functional GI disorders | journal = Gut | volume = 65| issue = 1| pages = 155–168| year = 2015 | pmid = 26194403 | doi = 10.1136/gutjnl-2015-309151 | quote = Functional gastrointestinal disorders (FGIDs) are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. The two most prevalent FGIDs, affecting up to 16–26% of worldwide population, are functional dyspepsia and irritable bowel syndrome. ... It is well established that mast cell activation can generate epithelial and neuro-muscular dysfunction and promote visceral hypersensitivity and altered motility patterns in FGIDs, postoperative ileus, food allergy and inflammatory bowel disease.<br /> ▸ Mast cells play a central pathophysiological role in IBS and possibly in functional dyspepsia, although not well defined.<br /> ▸ Increased mast cell activation is a common finding in the mucosa of patients with functional GI disorders. ...<br /> ▸ Treatment with mast cell stabilisers offers a reasonably safe and promising option for the management of those patients with IBS non-responding to conventional approaches, though future studies are warranted to evaluate efficacy and indications.| doi-access = free }}</ref><ref name="Mast cell mediators - eoxins">{{cite journal | vauthors = Moon TC, Befus AD, Kulka M | title = Mast cell mediators: their differential release and the secretory pathways involved | journal = Front Immunol | volume = 5 | pages = 569 | year = 2014 | pmid = 25452755 | pmc = 4231949 | doi = 10.3389/fimmu.2014.00569 | quote = Two types of degranulation have been described for MC: piecemeal degranulation (PMD) and anaphylactic degranulation (AND) (Figures 1 and 2). Both PMD and AND occur in vivo, ex vivo, and in vitro in MC in human (78–82), mouse (83), and rat (84). PMD is selective release of portions of the granule contents, without granule-to-granule and/or granule-to-plasma membrane fusions. ... In contrast to PMD, AND is the explosive release of granule contents or entire granules to the outside of cells after granule-to-granule and/or granule-to-plasma membrane fusions (Figures 1 and 2). Ultrastructural studies show that AND starts with granule swelling and matrix alteration after appropriate stimulation (e.g., FcεRI-crosslinking).| doi-access = free }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F1/ Figure 1: Mediator release from mast cells] {{webarchive|url=https://web.archive.org/web/20180429024530/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F1/ |date=29 April 2018 }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F2/ Figure 2: Model of genesis of mast cell secretory granules] {{webarchive|url=https://web.archive.org/web/20180429024530/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F2/ |date=29 April 2018 }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F3/ Figure 3: Lipid body biogenesis] {{webarchive|url=https://web.archive.org/web/20180429024530/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/figure/F3/ |date=29 April 2018 }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/table/T2/ Table 2: Stimuli-selective mediator release from mast cells] {{webarchive|url=https://web.archive.org/web/20180429024530/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/table/T2/ |date=29 April 2018 }}</ref>
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