Table 2.

Main categories of human mast cell- (MC-) derived mediators and their well-known topical effects.

Mediator category	Selected overall profile of the local activities	References
Preformed in MC secretory granules
Proteases:  Tryptases  Chymases  Carboxypeptidase A  Cathepsin G  Renin  Granzyme B	Neutral proteases play dual roles in inflammatory states depending on immunologic context, exerting proinflammatory and protective effects by activation/inhibition of the multiple respective cytokines within the signaling pathways; these activities result from proteolytic properties including angiotensin converting enzyme (ACE) activity, broad-spectrum antibacterial action against Gram-negative and Gram-positive bacteria; extracellular matrix (ECM) breakdown at inflammatory sites, ability to degrade some neuropeptides and toxins (neurotoxins), cleavage of receptors, platelet activation, and induction of airway submucosal gland secretion	Galli et al. 2020 [92]; Silver et al. 2004 [93]; Maaninka et al. 2018 [94]; Heutinck et al. 2010 [95]; Peljer et al. 2007 [96]; Peljer et al. 2010 [97]; Caughey 2016 [98]; Wang et al. 2014 [99]
Biogenic amines:
Histamine	Histamine action is mediated by histamine receptors H1, H2, H3, and H4 expressed in target cells; typical effects of histamine release include increased venular permeability with cutaneous flushing (H1, H2), increased heart rate and cardiac output (H1), bronchoconstriction (H1), increased mucus production in airways, nasal (H1) or generalized (H2), increased gastric acid secretion (H2), positive chemotaxis of neutrophils, T cells and eosinophils (H1) or neutrophil and eosinophil influx inhibition (H2), autoregulation of histamine release in brain (presynaptic H3), modulation of T helper type 2 (Th2) cell responses (H4)	Tiligada and Ennis 2020 [100]; Walter & Stark 2012 [101]; Thangham et al. 2018 [102]; Hattori et al. 2017 [103]
Serotonin (5-HT)	Serotonin is produced in human MCs during fetal development (e.g., placental MCs) and, to a lesser degree, in adult life; mastocytosis may induce 5-HT production in MCs; 5-HT signaling affects fetal brain development and placenta-derived 5-HT may be important for normal fetal brain development; 5-HT from MCs contributes to behavioral and physiological functions of the hippocampus	Bonnin and Levitt 2011 [104]; Ranzil et al. 2019 [105]; Kushnir-Sukhov et al. 2007 [106]; Ritter et al. 2012 [107]; Nautiyal et al. 2012 [108]
Proteoglycans:
Heparin  Heparin sulfate  Chondroitine sulfate  Dermatan sulfate  Serglycin proteoglycan	The proteoglycan serglycin carries an array of glycosaminoglycan side chains, sometimes heparin, sometimes chondroitin or dermatan sulphate. The members of proteoglycan family play essential role in regulation of MC granule storage and the release of secretory granule compounds, having an impact on the fate of the respective compounds after degranulation, affect the enzymatic properties of MC proteases and may promote apoptosis. Following MC degranulation heparin is probably involved in regulation of interstitial clotting but not in clotting in the vessels	Rönnberg et al. 2012 [109]; Mulloy et al. 2017 [110]; Zehnder and Galli 1999 [111]
De novo synthesized lipid mediators derived from arachidonic acid (eicosanoids)  Prostaglandins (PGs)  Leukotrienes (LTs)  Platelet activating factor (PAF)	At a tissue level, PGD2, the major PG produced by activated MCs and cysteinyl LTs (LTC4 and its active metabolites LTD4 and LTE4, as well as far lesser amounts of LTB4) produce increased vascular permeability, inflammation, pain, bronchoconstriction, increased uterine activity and vasoconstriction or vasodilation; PAF possesses high chemoattractant activity to neutrophils, eosinophils, monocytes, and macrophages and stimulates cytokine production by macrophages;	Sahid and Kiyoi 2020 [112]; Liu et al. 2017 [113]; Nakamura and Murata 2018 [114]; Theoharides et al. 2012 [115]
Cytokines including chemokines (selected)  Interleukins: IL-1, IL-3 ,IL-4, IL-5, IL-8,IL-9, IL-10, IL-31, IL-33  Growth factors: TNF-α, TGF-β1, TGF-β2, NGF, SCF, PDGF, VEGF, GM-CSF  Chemokines: CCL2, CXCL8 (IL-8), CX3CL1,	MCs release multifunctional cytokines involved in recruitment and activation of other cells participating in immune and inflammatory response; the cytokine profile heterogeneity reflects the differences in the secretory granule protease phenotypes between MCs and the tissue localization; depending on the stimulus, MCs calibrate their pattern of cytokine release, and as the immunoregulatory cells, can alter their response ranging from pro-inflammatory to anti-inflammatory	Elieh Ali Komi et al. 2020 [116]; Frossi et al. 2018 [9]; Moon et al. 2014 [117]