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| MC localization | Modulated physiological or pathological process | Characteristic features: MC number/distribution, MC mediators/receptors involved | Related complication, condition, or disease | References |
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| Ovary | Folliculogenesis, ovarian follicle selection, growth and ovulation | ↑ MC number in the human ovarian medulla/stroma during the proliferative phase; ovarian MCs correspond with interleukin 8 (IL-8) staining cells; exogenous IL-8 induces a similar increase in follicular growth to that produced by the luteinizing hormone (LH) surge; MC-derived histamine may regulate the development of ovarian follicles by apoptosis | Numerous primary or undeveloped ovarian follicles, anovulation | Goto et al. 1997 [15]; Szukiewicz et al. 2007 [16]; Field et al. 2014 [17]; Szukiewicz et al. 2007 [18] |
| Ovulation | MCs-derived histamine stimulates ovarian contractility, ovulation and follicular progesterone secretion; ↑ expressions of histamine H1 and H2 receptors in the preovulatory period within the growing ovarian follicles | Ovulatory disorders | Krishna et al. 1989 [19]; Szukiewicz et al. 2006 [20] |
| Ovulation and luteinization | Histamine and TNF-α release from degranulating stores (MCs within follicular wall) during ovulation | Ovulatory disorders and/or corpus luteum dysfunction | Field et al. 2014 [17]; Galvão et al. 2018 [21] |
| Altered neuroimmune communication | ↓ MC number in polycystic and ↓↓↓ MC number in postmenopausal ovaries with accompanying increase in nerve fibers in the corticomedullary region; more tryptase-positive MCs than chymase-positive MCs in the interstitial cortex and the medulla of polycystic ovaries (PCO) compared to normal cyclic ovaries; nerve growth factor (NGF) production by MCs suggests an interaction between MCs and nerve fibers via high affinity NGF tyrosine kinase receptor TrkA and low affinity receptor p75NTR | Polycystic ovary syndrome (PCOS); menopause | Heider et al. 2001 [22]; Krishna et al. 2001 [23]; Chang et al. 2019 [24] |
| Peritumoral MC infiltration | ↑ number of activated MC promotes tumor growth and spread by the release of proangiogenic factors (e.g., VEGF), degradation of the extracellular matrix (e.g., proteases), and direct and indirect immune suppression (e.g., IL-10 and TGF-β1) | Ovarian cancer progression | Chan et al. 2005 [25]; Oldford and Marshall 2015 [26]; Komi and Redegeld 2020 [27] |
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| Fallopian tube | Microcirculation of blood within fallopian tube wall | MCs regulate the microcirculatory blood stream of the fallopian tubes through release of vasoactive and angiogenic factors; volume and degree of the MC degranulation depends on the menstrual cycle phase, age and part of the fallopian tube. | Changes in the net luminal fluid secretion and absorption during the menstrual cycle | Glukhovets et al. 1980 [28] |
| Foreign body inflammatory response | In contraceptive intrauterine devices (IUD) users ↑ MC number were reported both in the muscularis externa and the lamina propria of the tubal wall; most MCs of the muscularis externa were more closely related to smooth muscle cells than to blood vessels. | Increased risk of pelvic inflammatory disease and the ectopic pregnancies amongst women using IUD | Sandvei R et al. 1986 [29] |
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| Peritoneal fluid | Endometriosis | ↑ MC count with increased release of chemoattractant cytokines, such as IL-8 and the monocyte chemoattractant protein-1 (MCP-1/CCL2); severity of endometriosis is positively correlated with the increase of both IL-8 and MCP-1/CCL2 in peritoneal fluid.
MCs mediators may directly suppress sperm motility; sperm interaction with the MC (LAD2) surface induces MC-degranulation in the peritoneal fluid of endometriosis patients. | Pelvic pain, endometriosis-related dysmenorrhea, growth of endometriotic foci with inflammatory response and peritoneal adhesions, infertility
Endometriosis associated infertility by suppression sperm cell function including motility | Oral et al. 1996 [30]; Broi et al. 2019 [31]
Menzies et al. 2011 [13]; Borelli et al. 2019 [32]; Broi et al. 2019 [31] |
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| Uterus: endometrium/decidua+myometrium | Endometrial proliferation | ↑ uterine MC counts in the menstrual and late secretory stages of the menstrual cycle; the pattern of MC cell ultrastructure is not associated with a particular tissue component in the uterine wall at any stage of the menstrual cycle; total degranulation of MCs is not observed during menstruation; in the late menstrual phase, degranulation by vacuolation and extensive invagination take place in the endometrial/myometrial junction and in the myometrium | Changes in functional status and secretory activity of MC within the endometrium during proliferative secretory and premenstrual stages of the menstrual cycle | Drudy et al. 1991 [33]; Sivridis et al. 2001 [34] |
| Postmenopausal endometrium | ↓ MC number; large numbers of MCs in the myometrial side of the endometrial/myometrial junction and in the deeper layers of the myometrium; no invagination of the MC membrane and lack of MCs with particulate granules suggest no impact on the functional layer of endometrium | Postmenopausal status of the functional layer within uterine mucous membrane | Drudy et al. 1991 [33] |
| Increased endometrial proliferation | Hyperactivation of MCs; >7-fold increase in the numbers of activated MCs expressing tryptase in endometrial polyps; ↑ densities of all MC types compared to normal endometrium; ↑ numbers of chymase+ and c-Kit+ endometrial MCs | Formation of endometrial polyps and polyp-related abnormal uterine bleeding or infertility | Al-Jefout et al. 2009 [35]; El-Hamarneh et al. 2013 [36] |
| Implantation | Estradiol (E2) and progesterone (P4)—governed migration of MCs from the periphery to the uterus and MC degranulation with the release of key factors (e.g., histamine, tryptase, VEGF, and metalloproteinases (MMPs)) during the embryo implantation in the posterior superior wall of the uterus; MC-derived histamine promoting trophoblast invasion, growth, and the expression of adhesion molecules; ↑ MC count within the entire layers of the endometrium with proinflammatory milieu in recurrent pregnancy loss (e.g., proven role of TNF-α excess in abortion). | Normal implantation, implantation-stage early abortion or recurrent pregnancy loss | Jensen et al. 2010 [37]; Elieh Ali Komi D et al. 2020 [38], Woidacki et al. 2014 [39]; Saito 2005 [40]; Matsuno et al. 2019 [41] |
| Implantation and placenta formation | Decidual MCs show an FcεRIα-positive (+)Kit(+)tryptase(+)chymase(+) phenotype; a larger proportion of tryptase(+); decidual MCs of parous women express a human-specific protein killer cell Ig-like receptor (KIR) 2DL4 (CD158d), a receptor for human leukocyte antigen G (HLA-G) expressed on human trophoblasts; KIR2DL4 stimulation with agonistic antibodies and recombinant HLA-G protein may enhance establishment of pregnancy by induction of leukemia inhibitory factor (LIF) and serine proteases release from MCs, in addition to suppressing mast-cell-mediated allergic/inflammatory reactions (downregulation of the Kit-mediated and FcɛRI-mediated responses); histamine from MCs is involved in differentiation of trophoblast cells toward extravillous, endovascular trophoblasts by stimulation of integrin αV-β3 (a vitronectin receptor) expression on trophoblast cells | Establishing pregnancy via killer cell Ig-like Receptor (KIR2DL4) expressed on the surface of decidual MCs; invasion of the uterine wall and the spiral arteries by extravillous trophoblasts (interstitial and endovascular invasions, respectively) | Derbala et al. 2018 [42]; Ueshima et al. 2018 [43]; Kataoka et al. 2020 [44]; Szewczyk et al. 2005 [45] |
| Foreign body inflammatory response | ↑ density of MCs in the endometrium of contraceptive intrauterine devices (IUD) users after 3 to 24 months’ use of IUD, independent of IUD type | Changed inflammatory cytokine profiles of endometrium at peri-implantation period corresponding to a contraceptive effect of IUD | Yin et al. 1993 [46]; Chou et al. 2015 [47] |
| Contractile activity | ↑ density of MCs in pregnant vs. non-pregnant myometrium; tryptase(+)/chymase(+) MCs are predominant in nonpregnant myometrium, whereas tryptase(+) MC dominate in pregnant myometrium; histamine H1 receptor antagonists partially inhibit uterine contractions; uterine MC degranulation, or the effects of their mediators, modulates contractility of pregnant uterus | Term or preterm uterine contractions including abortion and preterm/term delivery | Garfield et al. 2006 [48]; Bytautiene et al. 2004 [49]; Szukiewicz et al. 1995 [50] |
| Endothelin-1 (ET-1) production in the myometrium | MC-derived chymase is included in the chymase–ET-1 system operating in the myometrium during pregnancy; the number of MCs and production of ET-1 are significantly higher in myometrium from patients with severe preeclampsia compared to those from normal pregnant women | Chymase-dependent production of ET-1 in the myometrium during normal pregnancy and preeclampsia | Mitani et al. 2002 [51]; D’Orléans-Juste et al. 2008 [52] |
| Cervical ripening | Increased influx of MCs to the cervix during pregnancy; physiological or pathological stimulation of the secretory activity of cervical MCs may lead to the local increase in a number of MC-specific proteases, including the neutral proteases chymase, tryptase, and carboxypeptidase A. | Cervical tissue remodeling: in first trimester symptomatic miscarriage, in term/preterm pregnancy (contributing to term/preterm delivery), and in the postpartum period. | Elieh et al. 2020 [38]; Norström et al. 2019 [53]; Saito 2005 [40] |
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| Placenta | Angiogenesis | Placental MCs are an important source of potent proangiogenic factors (e.g., histamine, VEGF, bFGF, TGF-beta, TNF-alpha, and IL-8) and a source of extracellular matrix-degrading proteinases; changes in both the number of MCs and angiogenesis mediator concentrations were reported in placental tissue pathologies including diabetes and fetal growth restriction (FGR); ↑ placental expression of histamine H4 receptors in diabetes may enhance MC chemotaxis towards angiogenic sites. | Normal placental vascularization; defective and incomplete placental vascularization in IUGR; hypervascularization in diabetes mellitus | Kurihara-Shimomura et al. 2020 [54]; de Souza Junior et al. 2015 [55]; Szukiewicz et al. 1999 [56]; Szukiewicz et al. 2003 [57]; Szewczyk et al. [58] |
| Trophoblast invasion and spiral artery remodeling | MCs are important for proper development of the placental bed; ↑ chymase expression and activity in placental trophoblasts and in the maternal vascular endothelium in pregnancy induced hypertension; differential MC distribution and corresponding changes in the concentration of histamine are involved in the defective placental vascularization in preeclamptic placentas; both ↑ and ↓ MC numbers were reported in the villous part of the placenta in preeclampsia; unlike in normal placentae, in preeclamptic placentae histamine does not stimulate expression of integrin αv-β3 which is the necessary integrin to ensure trophoblast invasiveness. | Normal placental vascular bed formation; pregnancy-induced hypertension including the most prevalent hypertensive disorders of pregnancy: preeclampsia and eclampsia; FGR caused by insufficient remodeling of spiral arteries | Faas and De Vos 2018 [59]; Wang and Alexander 2013 [60]; Szewczyk et al. 2012 [61]; Szukiewicz et al. 1999 [62]; Mitani et al. 2002 [51]; Szewczyk et al. 2008 [63]; Meyer et al. 2017 [64] |
| Apoptosis | MC-derived histamine inhibits the apoptotic activity in trophoblast cells via histamine H1 receptor and further influences the process of trophoblast invasion and differentiation. | Placental apoptosis and related differentiation of the trophoblast and placental turnover | Wu et al. 2012 [65]; Pyzlak et al. 2010 [66]; Szewczyk et al. 2005 [45]; Liu et al. 2004 [67] |
| Contractile activity of the uterus including initiation of labor | ↑ density of MCs near the fetal surface of the placenta and in connective tissue foci; contractile activity of the uterus during normal vaginal delivery decreases histamine concentration in the placental tissue near the maternal surface of the placenta; MC distribution in placental tissue and membranes as well the degree of their secretory activation influence contractile activity of the uterus in health and disease. | Normal initiation of labor at term and premature birth with preterm onset of the contractile activity of the uterus | Szukiewicz et al. 1995 [50]; Needham et al. 2016 [68] |
| Allergic reaction within the human placenta | ↑ MC number and/or increased level of MC activation result in high levels of MC mediators in placental tissue in allergic mothers; allergen-induced placental cytokine and chemokine release include histamine, CXCL10, CXCL11, CCL17, CCL22, IL-6, and TNF. | Allergens induce placental cytokines and chemokines distinctly in allergic and healthy mothers influencing the prenatal development of the immune system; increased rate of immune disorders in childhood including allergies should may occur | Abelius et al. 2014 [69]; Mikkelsen et al. 1994 [70]; Straubinger et al. 2014 [71], Papadogiannakis et al. 2019 [72] |
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| Endometrial tissue outside the uterine cavity | Pain induction and mediation | ↑ MC number and ↑ number of degranulating MCs in endometriotic foci compared to nonaffected tissues; cross-talk between MCs and neurons is responsible for pain mediation; MCs may contribute to the development of pain and hyperalgesia in endometriosis, possibly by a direct effect on nerve structures; ↑ E2 concentrations may be a key factor for degranulation and recruitment of MCs in ovarian endometriomas with a key role in endometriosis-associated dysmenorrhea. | Endometriosis-related chronic and neuropathic pain including dysmenorrhea | Anaf et al. 2006 [73]; Zhu et al. 2019 [74]; D’Cruz et al. 2007 [75]; Zhu et al. 2018 [76] |
| Fibrosis and fibrotic scarring | Invasion of MCs, degranulation, and proliferation of interstitial component are observed in endometriotic lesions; the Janus kinase 3 (JAK3) is abundantly expressed in MCs and is required for the full expression of high-affinity IgE receptor-mediated MC inflammatory sequelae including fibrosis and increased risk of adhesion development; ↑ numbers of activated MCs in endometriosis are strongly positive for corticotropin-releasing hormone (CRH) and urocortin (Ucn)—the peptides activating MCs and contributing to the fibrosis and inflammation. | Fibrous adhesions in endometriotic lesions | Anaf et al. 2006 [73]; Kirchhoff et al. 2012 [77]; Kempuraj et al. 2004 [78] |
| Angiogenesis | Activation of MCs in situ causes local MC-mediated angiogenesis; C-C Motif Chemokine 8 (CCL8) promotes both in vitro and in vivo angiogenesis via the CC chemokine receptor 1 (CCR1); ↑ CCL8 in MCs was reported in the coculture with endometrial cells; ectopic endometrium and the serum of patients with endometriosis revealed ↑ CCL8 expressions; ↑ CCR1 perivascular expression was reported in the ectopic endometrium in ovarian endometriomas. | Ectopic angiogenesis in endometriotic foci | Norrby 1995 [79]; Xue et al. 2020 [80]; Li et al. 2020 [81]; Binda et al. 2017 [82] |
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