title: Retinoic Acid Negatively Impacts Proliferation and MCTCSpecific Attributes of Human Skin Derived Mast Cells, but Reinforces Allergic Stimulability.
abstract: The Vitamin-A-metabolite retinoic acid (RA) acts as a master regulator of cellular programs. Mast cells (MCs) are primary effector cells of type-I-allergic reactions. We recently uncovered that human cutaneous MCs are enriched with RA network components over other skin cells. Yet, direct experimental evidence on the significance of the RA-MC axis is limited. Here, skin-derived cultured MCs were exposed to RA for seven days and investigated by flow-cytometry (BrdU incorporation, Annexin/PI, FcεRI), microscopy, RT-qPCR, histamine quantitation, protease activity, and degranulation assays. We found that while MC size and granularity remained unchanged, RA potently interfered with MC proliferation. Conversely, a modest survival-promoting effect from RA was noted. The granule constituents, histamine and tryptase, remained unaffected, while RA had a striking impact on MC chymase, whose expression dropped by gene and by peptidase activity. The newly uncoveredMRGPRX2performed similarly to chymase. Intriguingly, RA fostered allergic MC degranulation, in a way completely uncoupled from FcεRI expression, but it simultaneously restricted MRGPRX2-triggered histamine release in agreement with the reduced receptor expression. Vitamin-A-derived hormones thus re-shape skin-derived MCs numerically, phenotypically, and functionally. A general theme emerges, implying RA to skew MCs towards processes associated with (allergic) inflammation, while driving them away from the skin-imprinted MCTC("MCs containing tryptase and chymase") signature (chymase, MRGPRX2). Collectively, MCs are substantial targets of the skin retinoid network.
authors.affiliation: Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany. magda.babina@charite.de.
authors.forename: Magda
authors.initials: M
authors.lastname: Babina
authors.affiliation: Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany. metin.artuc@charite.de.
authors.forename: Metin
authors.initials: M
authors.lastname: Artuc
authors.affiliation: Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany. sven.guhl@gmx.de.
authors.forename: Sven
authors.initials: S
authors.lastname: Guhl
authors.affiliation: Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany. torsten.zuberbier@charite.de.
authors.forename: Torsten
authors.initials: T
authors.lastname: Zuberbier
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology*; D019655:Quantitative Trait, Heritable; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology*; D014212:Tretinoin / Q000494:pharmacology*; D053802:Tryptases / Q000235:genetics / Q000378:metabolism
chemical_list: D017455:Receptors, IgE; D007073:Immunoglobulin E; D014212:Tretinoin; D006632:Histamine; D053802:Tryptases
keywords: IgER; cell cycle; chymase; mast cell; proliferation; retinoic acid; skin; tryptase