Abstract
Mast cells (MCs) occupy a central role in immunological as well as non-immunological processes as reflected in the variety of the mediators by which MCs influence other cells. Published lists of MC mediators have all shown only subsets—usually quite small—of the full repertoire. The full repertoire of MC mediators released by exocytosis is comprehensively compiled here for the first time. The compilation of the data is essentially based on the largely cytokine-focused database COPE®, supplemented with data on the expression of substances in human MCs published in several articles, plus extensive research in the PubMed database. Three hundred and ninety substances could be identified as mediators of human MCs which can be secreted into the extracellular space by activation of the MC. This number might still be an underestimate of the actual number of MC mediators since, in principle, all substances produced by MCs can become mediators because of the possibility of their release by diffusion into the extracellular space, mast cell extracellular traps, and intercellular exchange via nanotubules. When human MCs release mediators in inappropriate manners, this may lead to symptoms in any or all organs/tissues. Thus, such MC activation disorders may clinically present with a myriad of potential combinations of symptoms ranging from trivial to disabling or even life-threatening. The present compilation can be consulted by physicians when trying to gain clarity about MC mediators which may be involved in patients with MC disease symptoms refractory to most therapies.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Mast cells (MCs) are round, about 20 μm diameter cells of the immune system containing cytoplasmic granules variably filled with many messenger substances (mediators). They originate in hematopoietic tissue; white adipose tissue has been identified as a reservoir of MC precursors, too (Poglio et al. 2010). They are resident in all vascularized organs and tissues; the majority are located at the interfaces to the outside world, such as mucous membranes and skin. At these sites, MCs are best positioned to sense when tissues are under attack by potentially harmful pathogens (parasites, bacteria, viruses, venoms) and can act accordingly. In addition, MCs likely have many more underappreciated roles in the human homeostasis of organs that undergo continuous growth and remodeling such as hair follicles and bones, wound healing, disease response, tissue repair, and angiogenesis. They are sensors of hypoxemia, air pressure, vibratory stimuli, and light. In addition, MCs are an integral component of the stress response system (Afrin et al. 2016).
MCs developed more than 500 million years ago (Crivellato et al. 2015), i.e., before the development of adaptive immunity, suggesting that MCs act as effector immune cells and as regulatory immune cells and play central roles in both innate and adaptive immunity (Gri et al. 2012). Through evolution, MCs have become optimized for their already discovered functions such as regulatory control of homeostasis of the organism, potent effector cells of the immune system, and regulation of the functional interaction of the innate and adaptive immune system (Norrby 2022). It seems likely that many other MC mediators with their associated functions remain to be discovered.
The aim of the present survey is to provide all those working in the field of MCs, scientifically and clinically, with a comprehensive compilation of human MC mediators released by exocytosis that can be used as a reference work.
Methods
The compilation of the data is essentially based on the COPE® database (Ibelgaufts 2023), which also contains references that go beyond the references given in the tables herein. This database was last accessed in March 2023. These data were supplemented with data on the expression of proteins in human MCs which had been investigated by, and were published in, Liang et al. (2018), Motakis et al. (2014), Haenisch et al. (2013), Okayama (2005), Halloran et al. (2019), and Babina et al. (2004). In addition, the PubMed database was searched with the phrase human “mast cell*” mediator*. The selective information on the potential effects of the compiled mediators were taken from the GeneCards® database (https://www.genecards.org/).
Results
On the basis of the analyzed databases, 390 substances could be identified (Online Resource 1 and 2) which are formed intracellularly by human MCs and can be secreted by exocytosis into the extracellular space by activation of the MC and can induce effects in effector cells. In studies on murine MCs, another 55 substances have been identified (data not shown) as potential mediators. However, since these substances have not yet been detected in human MCs, they are not further considered as human MC mediators in the following. Each of the 390 potential mediators is able to induce several effects on effector cells (GeneCards®). Selected manifestations of MC activation have been linked to specific mediators (Table 1) as an example of using the data from Online Resource 1.
Understanding the autocrine/paracrine activation of MCs (Fig. 1) is essential for understanding the development of an acute MC mediator release episode (He et al. 2012). Therefore, Table 2 lists all mediators which are likely to induce, via 30 distinct receptor classes, autocrine activation of the releasing MC, and paracrine activation of other MCs in the proximity of the releasing MC. This finding agrees well with the clinical observation of acute to subacute activation phases of MCs beyond anaphylactic reactions. These 30 activating mechanisms are opposed only by seven autocrine/paracrine receptors that can inhibit MC activation (Table 2).
Two further phenomena could be important for MC activation: first, the possibility of reuptake of mediators released by the MCs for later re-exocytosis. Such reuptake of released mediators may not be accompanied by stimulation of the corresponding receptor because (1) the receptor may still be inactivated due to previous autocrine activation, and (2) reuptake may take place via receptor-independent specific reuptake mechanisms (e.g., transporters). Second, substances originally formed and released by other cells which were taken up and stored by the MCs can potentially act as MC mediators when subsequently released from the MCs (Table 3). The possibility of reuptake or uptake of substances or groups of substances into the MCs which then can act as mediators could be identified for 15 compounds (Table 3).
Discussion
The central role of MCs in immunological as well as non-immunological processes is reflected by the large number of mediators by which MCs may influence other cells (Lundequist and Pejler 2011). The profile of mediators and cytokines stored or produced de novo in MCs can markedly differ between and even within organs/tissues depending upon a wide array of macro- and micro-environmental factors including antigenic and physical stimuli. Although the number of MC mediators has been assumed to be large, there has not yet been any comprehensive compilation of human MC mediators. In this article, the known human MC mediators are comprehensively compiled for the first time. And indeed, the number of mediators, at least 390, turns out to be extraordinarily high compared to the number of messenger substances known to be formed and released by other cells. However, this number still might substantially underestimate the actual number of MC mediators, once one takes into consideration broader definitions of “mediatorˮ and broader definitions of effector mechanisms than we consider for our present purposes.
MC actions can be targeted very precisely. Occasionally, MCs release pre-stored mediators via classic non-selective whole-MC degranulation (as in anaphylaxis), but this is the exception, not the rule, in MC activation (Theoharides et al. 2007, 2023). Otherwise, anaphylactic reaction would occur consistently in every episode of MC activation, but this is obviously not the case. Rather than wholly degranulate, MCs much more commonly selectively release specific mediators, referred to as differential release (Table 4), i.e., release of the content of individual secretory granules or individual mediators without whole-MC degranulation (Theoharides et al. 1982). This process is distinct from “piecemeal degranulation” that has additionally been reported (Dvorak 2005). MCs can also form synapses for targeted secretion (Table 4).With regard to the possibility that, under certain circumstances, almost all molecules that can be produced by a MC might be able to act as mediators, four release options are of particular interest: (1) diffusion of substances into the extracellular space; (2) release of mRNA, microRNA, and proteins expressed in the MC by secretion of exosomes and vesicles (Savage et al. 2023), some of them containing KIT (Pfeiffer et al. 2022); (3) formation of nanotubules with exchange of intracellular material which seems to be involved in inducing apoptosis in cancer cells (Ahani et al. 2022); and (4) formation of MC extracellular traps (Möllerherm et al. 2016; Table 4). These four mechanisms, by which MCs can use almost any molecule as a mediator, underline the extraordinary role of these cells in our immune system. At the same time, this creates an almost insurmountable hurdle for precisely attributing specific clinical symptoms to specific messenger substances. This problem of assigning (a) certain MC mediator(s) to symptoms is further complicated by the fact that released MC mediators can maintain and enhance MC activation in autocrine and paracrine manners (Fig. 1), and additionally by the possibility of MCs taking up substances from their immediate environment and then re-releasing them. In this context, it has to be noted that MCs are able to survive even complete degranulation followed by regranulation (Iskarpatyoti et al. 2022). Interestingly, MCs have altered granule contents and structure after regranulation, likely depending on the trigger that had induced the degranulation (Friend et al. 1996; Iskarpatyoti et al. 2022, further references therein).
Clinical impact
It does not require a great imagination to envision that the very same mechanisms which enable MCs to protect the organism can wreak focused or multisystem havoc when uncontrolled, potentially causing a vast array of diseases, some of which might be quite severe. In this context, primary systemic MC disease (dominantly MC activation syndrome (MCAS)) is of particular interest for at least two reasons: (1) its prevalence of about 20% (Molderings et al. 2013; Maitland et al. 2020) represents a significant socio-economic problem; and (2) due to its epigenetic causation with transgenerational transmission (Molderings 2022), it tends to manifest in successive generations more severely and at steadily earlier ages, creating increasing treatment challenges. Systemic mast cell disease (also presently termed mast cell activation disease (MCAD)), in its assorted variants (including systemic mastocytosis and MCAS), is usually driven, at the level of the individual, by multiple stem cell germline and somatic mutations (emerging out of complex interactions between stressor-induced cytokine storms and a genome rendered insufficiently robust, by the aforementioned epigenetic variants, at repairing or eradicating induced mutations) leading directly or indirectly to inappropriate chronic constitutive and reactive activation of the affected MCs (Weinstock et al. 2021). Due to both their widespread distribution and the great heterogeneity of aberrant mediator expression patterns, symptoms may occur in all organs and tissues. Hence, the clinical presentation of MCAD disease is very diverse, with a myriad of combinations of symptoms, ranging in the severity of illness from trivial to disabling and even life-threatening (Afrin et al. 2016).
Perspective
The present survey of the potential MC mediators in the narrower sense (Online Resource 1 and 2) and broader sense (Table 4), together with the findings of autocrine and paracrine stimulation and the ability of the MC to (re)use substances it takes up as mediators, are not of interest merely to researchers. These tables can be consulted by attending physicians, too, when trying to gain clarity about MC mediators which may be involved in patients with MC disease symptoms which are often resistant to therapy, such as hyper-/hypotension, transient tachyarrhthmias, or migrating pain. Such a procedure might be extraordinarily effective if, based on the available tables and with the help of special computer programs to be developed, all the information contained in relevant databases such as GeneCards®, PubMed, EMBL’s European Bioinformatics Institute, Embase, Cochrane Library, and others could help link the symptoms in a patient to given mediator expression profiles, thereby hopefully providing personalized therapeutic insights. This might enable the selection of treatments (Molderings et al. 2016) more likely to help patients exhibiting specific MC-mediator-induced symptoms. Ultimately, though, routine performance in the clinical laboratory of MC-specific genome sequencing (using pipelines already in place in many laboratories for sequencing the tumor cells in biopsies, but re-tuned, likely based on strong CD117 expression, to select the MCs in the sample) will be needed to discover not only which mutational profiles reliably correlate with which symptom profiles but also which treatments will best address the phenotypes driven by particular mutational profiles.
Data availability
Not applicable
References
Afrin LB, Butterfield JH, Raithel M, Molderings GJ (2016) Often seen, rarely recognized: mast cell activation disease--a guide to diagnosis and therapeutic options. Ann Med 48:190–201. https://doi.org/10.3109/07853890.2016.1161231
Ahani E, Fereydouni M, Motaghed M, Kepley CL (2022) Identification and characterization of tunneling nanotubes involved in human mast cell FcεRI-mediated apoptosis of cancer cells. Cancers (Basel) 14:2944. https://doi.org/10.3390/cancers14122944
Alysandratos KD, Asadi S, Angelidou A, Zhang B, Sismanopoulos N, Yang H, Critchfield A, Theoharides TC (2012) Neurotensin and CRH interactions augment human mast cell activation. Plos One 7:e48934. https://doi.org/10.1371/journal.pone.0048934
Babina M, Guhl S, Stärke A, Kirchhof L, Zuberbier T, Henz BM (2004) Comparative cytokine profile of human skin mast cells from two compartments--strong resemblance with monocytes at baseline but induction of IL-5 by IL-4 priming. J Leukoc Biol 75:244–252. https://doi.org/10.1189/jlb.0403157
Bachelet I, Munitz A, Mankutad D, Levi-Schaffer F (2006) Mast cell costimulation by CD226/CD112 (DNAM-1/Nectin-2): a novel interface in the allergic process. J Biol Chem 281:27190–27196. https://doi.org/10.1074/jbc.M602359200
Bisogno T, Maurelli S, Melck D, De Petrocellis L, Di Marzo V (1997) Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem 272:3315–3323. https://doi.org/10.1074/jbc.272.6.3315
Braile M, Marcella S, Marone G, Galdiero MR, Varricchi G, Loffredo S (2021) The interplay between the immune and the endocannabinoid systems in cancer. Cells 10:1282. https://doi.org/10.3390/cells10061282
Carroll-Portillo A, Surviladze Z, Cambi A, Lidke DS, Wilson BS (2012) Mast cell synapses and exosomes: membrane contacts for information exchange. Front Immunol 3:46. https://doi.org/10.3389/fimmu.2012.00046
Chen K, Popel AS (2007) Vascular and perivascular nitric oxide release and transport: biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3). Free Radic Biol Med 42:811–822. https://doi.org/10.1016/j.freeradbiomed.2006.12.007 PMID: 17320763
Crivellato E, Travan L, Ribatti D (2015) The phylogenetic profile of mast cells. Methods Mol Biol 1220:11–27. https://doi.org/10.1007/978-1-4939-1568-2_2
D’Incà F, Pucillo CE (2015) Exosomes: tiny clues for mast cell communication. Front Immunol 6:73. https://doi.org/10.3389/fimmu.2015.00073 PMID: 25741344
Dellinger A, Zhou Z, Norton SK, Lenk R, Conrad D, Kepley CL (2010) Uptake and distribution of fullerenes in human mast cells. Nanomed 6:575–582. https://doi.org/10.1016/j.nano.2010.01.008
Dvorak AM (2005) Piecemeal degranulation of basophils and mast cells is effected by vesicular transport of stored secretory granule contents. Chem Immunol Allergy 85:135–184. https://doi.org/10.1159/000086516
Ekström K, Valadi H, Sjöstrand M, Malmhäll C, Bossios A, Eldh M, Lötvall J (2012) Characterization of mRNA and microRNA in human mast cell-derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells. J Extracell Vesicles 1:18389. https://doi.org/10.3402/jev.v1i0.18389
Elishmereni M, Alenius HT, Bradding P, Mizrahi S, Shikotra A, Minai-Fleminger Y, Mankuta D, Eliashar R, Zabucchi G, Levi-Schaffer F (2011) Physical interactions between mast cells and eosinophils: a novel mechanism enhancing eosinophil survival in vitro. Allergy 66:376–385. https://doi.org/10.1111/j.1398-9995.2010.02494.x
Friend DS, Ghildyal N, Austen KF, Gurish MF, Matsumoto R, Stevens RL (1996) Mast cells that reside at different locations in the jejunum of mice infected with Trichinella spiralis exhibit sequential changes in their granule ultrastructure and chymase phenotype. J Cell Biol 135:279–290. https://doi.org/10.1083/jcb.135.1.279
Garcia-Rodriguez KM, Bahri R, Sattentau C, Roberts IS, Goenka A, Bulfone-Paus S (2020) Human mast cells exhibit an individualized pattern of antimicrobial responses. Immun Inflamm Dis 8:198–210. https://doi.org/10.1002/iid3.295
Gri G, Frossi B, D'Inca F, Danelli L, Betto E, Mion F, Sibilano R, Pucillo C (2012) Mast cell: an emerging partner in immune interaction. Front Immunol 3:120. https://doi.org/10.3389/fimmu.2012.00120 PMID: 22654879
Haenisch B, Herms S, Molderings GJ (2013) The transcriptome of the human mast cell leukemia cells HMC-1.2: an approach to identify specific changes in the gene expression profile in KITD816V systemic mastocytosis. Immunol Res 56:155–162. https://doi.org/10.1007/s12026-013-8391-1
Halloran KM, Parkes MD, Chang J, Timofte IL, Snell GI, Westall GP, Hachem R, Kreisel D, Trulock E, Roux A, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Halloran PF (2019) Molecular assessment of rejection and injury in lung transplant biopsies. J Heart Lung Transplant 38:504–513. https://doi.org/10.1016/j.healun.2019.01.1317
He S, McEuen AR, Blewett SA, Li P, Buckley MG, Leufkens P, Walls AF (2003) The inhibition of mast cell activation by neutrophil lactoferrin: uptake by mast cells and interaction with tryptase, chymase and cathepsin G. Biochem Pharmacol 65:1007–1015. https://doi.org/10.1016/s0006-2952(02)01651-9
He S, Zhang H, Zeng X, Yang P (2012) Self-amplification mechanisms of mast cell activation: a new look in allergy. Curr Mol Med 12:1329–1339. https://doi.org/10.2174/156652412803833544
Higashi N, Maeda R, Sesoko N, Isono M, Ishikawa S, Tani Y, Takahashi K, Oku T, Higashi K, Onishi S, Nakajima M, Irimura T (2019) Chondroitin sulfate E blocks enzymatic action of heparanase and heparanase-induced cellular responses. Biochem Biophys Res Commun 520:152–158. https://doi.org/10.1016/j.bbrc.2019.09.126
Huszti Z (2003) Histamine uptake into non-neuronal brain cells. Inflamm Res 52(Suppl 1):S03–S06. https://doi.org/10.1007/s000110300028
Ibelgaufts H (2023) COPE -Cytokines & Cells Online Pathfinder Encyclopaedia. http://www.cells-talk.com/index.php/page/about. Last accessed March 2023
Iskarpatyoti JA, Shi J, Abraham MA, Rathore APS, Miao Y, Abraham SN (2022) Mast cell regranulation requires a metabolic switch involving mTORC1 and a glucose-6-phosphate transporter. Cell Rep 40:111346. https://doi.org/10.1016/j.celrep.2022.111346
Jayapal M, Tay HK, Reghunathan R, Zhi L, Chow KK, Rauff M, Melendez AJ (2006) Genome-wide gene expression profiling of human mast cells stimulated by IgE or FcepsilonRI-aggregation reveals a complex network of genes involved in inflammatory responses. BMC Genomics 7:210. https://doi.org/10.1186/1471-2164-7-210
Jiang Y, Kanaoka Y, Feng C, Nocka K, Rao S, Boyce JA (2006) Cutting edge: Interleukin 4-dependent mast cell proliferation requires autocrine/intracrine cysteinyl leukotriene-induced signaling. J Immunol 177:2755–2759. https://doi.org/10.4049/jimmunol.177.5.2755
Kim DK, Cho YE, Komarow HD, Bandara G, Song BJ, Olivera A, Metcalfe DD (2018) Mastocytosis-derived extracellular vesicles exhibit a mast cell signature, transfer KIT to stellate cells, and promote their activation. Proc Natl Acad Sci U S A 115:E10692–E10701. https://doi.org/10.1073/pnas.1809938115
Klein O, Sagi-Eisenberg R (2019) Anaphylactic degranulation of mast cells: focus on compound exocytosis. J Immunol Res 2019:9542656. https://doi.org/10.1155/2019/9542656
Kritikou E, Kuiper J, Kovanen PT, Bot I (2016) The impact of mast cells on cardiovascular diseases. Eur J Pharmacol 778:103–115. https://doi.org/10.1016/j.ejphar.2015.04.050
Le DD, Schmit D, Heck S, Omlor AJ, Sester M, Herr C, Schick B, Daubeuf F, Fähndrich S, Bals R, Frossard N, Al Kadah B, Dinh QT (2016) Increase of mast cell-nerve association and neuropeptide receptor expression on mast cells in perennial allergic rhinitis. Neuroimmunomodulation 023:261–270. https://doi.org/10.1159/000453068
Liang Y, Qiao L, Peng X, Cui Z, Yin Y, Liao H, Jiang M, Li L (2018) The chemokine receptor CCR1 is identified in mast cell-derived exosomes. Am J Transl Res 10:352–367
Lundequist A, Pejler G (2011) Biological implications of preformed mast cell mediators. Cell Mol Life Sci 68:965–975. https://doi.org/10.1007/s00018-010-0587-0
Maitland A, Brock I, Reed W (2020) Immune dysfunction, both mast cell activation disorders and primary immune deficiency, is common among patients with hypermobile spectrum disorder (HSD) or hypermobile type Ehlers Danlos Syndrome (hEDS). In Proceedings of the EDS ECHO Summit, October 2, 2020; session 12, poster number 001, available online: https://www.ehlers-danlos.com/wp-content/uploads/2020/09/Poster-001-FINAL-A-Maitland-et-al-EDS-ECHO-SUMMIT-Oct-2020.pdf
Marquardt DL, Gruber HE, Wasserman SI (1984) Adenosine release from stimulated mast cells. Proc Natl Acad Sci U S A 81:6192–6196. https://doi.org/10.1073/pnas.81.19.6192
McHale C, Mohammed Z, Deppen J, Gomez G (2018) Interleukin-6 potentiates FcεRI-induced PGD2 biosynthesis and induces VEGF from human in situ-matured skin mast cells. Biochim Biophys Acta Gen Subj 1862:1069–1078. https://doi.org/10.1016/j.bbagen.2018.01.020
Miralda I, Samanas NB, Seo AJ, Foronda JS, Sachen J, Hui Y, Morrison SD, Oskeritzian CA, Piliponsky AM (2023) Siglec-9 is an inhibitory receptor on human mast cells in vitro. J Allergy Clin Immunol S0091-6749(23):00511-0. https://doi.org/10.1016/j.jaci.2023.04.007
Molderings GJ (2022) Systemic mast cell activation disease variants and certain genetically determined comorbidities may be consequences of a common underlying epigenetic disease. Med Hypotheses 163:110862. https://doi.org/10.1016/j.mehy.2022.110862
Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, Nöthen MM (2013) Familial occurrence of systemic mast cell activation disease. Plos One 8:e76241. https://doi.org/10.1371/journal.pone.0076241
Molderings GJ, Haenisch B, Brettner S, Homann J, Menzen M, Dumoulin FL, Panse J, Butterfield J, Afrin LB (2016) Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedeberg's Arch Pharmacol 389:671–694. https://doi.org/10.1007/s00210-016-1247-1 Epub 2016 Apr 30
Möllerherm H, von Köckritz-Blickwede M, Branitzki-Heinemann K (2016) Antimicrobial activity of mast cells: role and relevance of extracellular DNA traps. Front Immunol 7:265. https://doi.org/10.3389/fimmu.2016.00265
Moon TC, Befus AD, Kulka M (2014) Mast cell mediators: their differential release and the secretory pathways involved. Front Immunol 5:569. https://doi.org/10.3389/fimmu.2014.00569
Motakis E, Guhl S, Ishizu Y, Itoh M, Kawaji H, de Hoon M, Lassmann T, Carninci P, Hayashizaki Y, Zuberbier T, Forrest AR, Babina M, FANTOM consortium (2014) Redefinition of the human mast cell transcriptome by deep-CAGE sequencing. Blood 123:e58–e67. https://doi.org/10.1182/blood-2013-02-483792
Niederhoffer N, Levy R, Sick E, Andre P, Coupin G, Lombard Y, Gies JP (2009) Amyloid beta peptides trigger CD47-dependent mast cell secretory and phagocytic responses. Int J Immunopathol Pharmacol 22:473–483. https://doi.org/10.1177/039463200902200224
Noordenbos T, Blijdorp I, Chen S, Stap J, Mul E, Cañete JD, Lubberts E, Yeremenko N, Baeten D (2016) Human mast cells capture, store, and release bioactive, exogenous IL-17A. J Leukoc Biol 100:453–462. https://doi.org/10.1189/jlb.3HI1215-542R
Norrby K (2022) Do mast cells contribute to the continued survival of vertebrates? APMIS 130:618–624. https://doi.org/10.1111/apm.13264 PMID: 35869669
Okayama Y (2005) Mast cell-derived cytokine expression induced via Fc receptors and Toll-like receptors. Chem Immunol Allergy 87:101–110. https://doi.org/10.1159/000087574
Oskeritzian CA, Alvarez SE, Hait NC, Price MM, Milstien S, Spiegel S (2008) Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions. Blood 111:4193–4200. https://doi.org/10.1182/blood-2007-09-115451
Paruchuri S, Jiang Y, Feng C, Francis SA, Plutzky J, Boyce JA (2008) Leukotriene E4 activates peroxisome proliferator-activated receptor gamma and induces prostaglandin D2 generation by human mast cells. J Biol Chem 283:16477–16487. https://doi.org/10.1074/jbc.M705822200
Peng WM, Maintz L, Allam JP, Raap U, Gütgemann I, Kirfel J, Wardelmann E, Perner S, Zhao W, Fimmers R, Walgenbach K, Oldenburg J, Schwartz LB, Novak N (2013) Increased circulating levels of neurotrophins and elevated expression of their high-affinity receptors on skin and gut mast cells in mastocytosis. Blood 122:1779–1788. https://doi.org/10.1182/blood-2012-12-469882
Pfeiffer A, Petersen JD, Falduto GH, Anderson DE, Zimmerberg J, Metcalfe DD, Olivera A (2022) Selective immunocapture reveals neoplastic human mast cells secrete distinct microvesicle- and exosome-like populations of KIT-containing extracellular vesicles. J Extracell Vesicles 11:e12272. https://doi.org/10.1002/jev2.12272
Poglio S, De Toni-Costes F, Arnaud E, Laharrague P, Espinosa E, Casteilla L, Cousin B (2010) Adipose tissue as a dedicated reservoir of functional mast cell progenitors. Stem Cells 28:2065–2072. https://doi.org/10.1002/stem.523
Reinheimer T, Vogel P, Racké K, Bittinger F, Kirkpatrick CJ, Saloga J, Knop J, Wessler I (1998) Non-neuronal acetylcholine is increased in chronic inflammation like atopic dermatitis. Naunyn-Schmiedeberg’s Arch Pharmacol (Suppl) 358:R87
Savage A, Risquez C, Gomi K, Schreiner R, Borczuk AC, Worgall S, Silver RB (2023) The mast cell exosome-fibroblast connection: a novel pro-fibrotic pathway. Front Med (Lausanne) 10:1139397. https://doi.org/10.3389/fmed.2023.1139397
Schulman ES, Glaum MC, Post T, Wang Y, Raible DG, Mohanty J, Butterfield JH, Pelleg A (1999) ATP modulates anti-IgE-induced release of histamine from human lung mast cells. Am J Respir Cell Mol Biol 20:530–537. https://doi.org/10.1165/ajrcmb.20.3.3387
Shefler I, Salamon P, Mekori YA (2021) Extracellular vesicles as emerging players in intercellular communication: relevance in mast cell-mediated pathophysiology. Int J Mol Sci 22:9176. https://doi.org/10.3390/ijms22179176
Theoharides TC, Bondy PK, Tsakalos ND, Askenase PW (1982) Differential release of serotonin and histamine from mast cells. Nature 297:229–231. https://doi.org/10.1038/297229a0
Theoharides TC, Douglas WW (1978) Secretion in mast cells induced by calcium entrapped within phospholipid vesicles. Science 201:1143–1145. https://doi.org/10.1126/science.684435
Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 217:65–78. https://doi.org/10.1111/j.1600-065X.2007.00519.x
Theoharides TC, Perlman AI, Twahir A, Kempuraj D (2023) Mast cell activation: beyond histamine and tryptase. Expert Rev Clin Immunol 1-16. https://doi.org/10.1080/1744666X.2023.2200936. Epub ahead of print
Tsai SH, Takeda K (2016) Regulation of allergic inflammation by the ectoenzyme E-NPP3 (CD203c) on basophils and mast cells. Semin Immunopathol 38:571–579. https://doi.org/10.1007/s00281-016-0564-2
Weinstock LB, Pace LA, Rezaie A, Afrin LB, Molderings GJ (2021) Mast cell activation syndrome: a primer for the gastroenterologist. Dig Dis Sci 66:965–982. https://doi.org/10.1007/s10620-020-06264-9
Funding
Open Access funding enabled and organized by Projekt DEAL. The investigations were supported by a grant of the Förderclub Mastzellforschunge.V.
Author information
Authors and Affiliations
Contributions
G.J.M. and L.B.A. conceived and designed the research project and contributed to the analysis of the data. Both G.J.M. and L.B.A. wrote the manuscript. Both authors read and approved the manuscript. The authors confirm that no paper mill and artificial intelligence was used.
Corresponding author
Ethics declarations
Ethical approval
Not applicable
Competing interests
Dr. Molderings is chief medical officer of the start-up company MC Sciences, Ltd. Dr. Afrin is an uncompensated volunteer medical advisor to the start-up company MC Sciences Ltd.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Molderings, G.J., Afrin, L.B. A survey of the currently known mast cell mediators with potential relevance for therapy of mast cell-induced symptoms. Naunyn-Schmiedeberg's Arch Pharmacol 396, 2881–2891 (2023). https://doi.org/10.1007/s00210-023-02545-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-023-02545-y