title: The enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis.
abstract: Mast cells (MCs) mature locally, thus possessing tissue-dependent phenotypes for their critical roles in both protective immunity against pathogens and the development of allergy or inflammation. We previously reported that MCs highly express P2X7, a receptor for extracellular ATP, in the colon but not in the skin. The ATP-P2X7 pathway induces MC activation and consequently exacerbates the inflammation. Here, we identified the mechanisms by which P2X7 expression on MCs is reduced by fibroblasts in the skin, but not in the other tissues. The retinoic-acid-degrading enzyme Cyp26b1 is highly expressed in skin fibroblasts, and its inhibition resulted in the upregulation of P2X7 on MCs. We also noted the increased expression of P2X7 on skin MCs and consequent P2X7- and MC-dependent dermatitis (so-called retinoid dermatitis) in the presence of excessive amounts of retinoic acid. These results demonstrate a unique skin-barrier homeostatic network operating through Cyp26b1-mediated inhibition of ATP-dependent MC activation by fibroblasts.
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan; Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kurashima
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan; Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8561, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Amiya
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Fujisawa
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan; Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8561, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shibata
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8561, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kogure
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Hashimoto
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otsuka
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8561, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Laboratory for Cytokine Regulation, Research Center for Integrative Medical Science, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan; Division of Molecular Pathology, Research Institute for Biological Sciences, Tokyo University of Sciences, Chiba 278-0022, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan; Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8561, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Department of Microbiology and Immunology, Kobe University School of Medicine, Kobe 650-0017, Japan. Electronic address: kunisawa@nibio.go.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Kunisawa
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan; Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8561, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Electronic address: kiyono@ims.u-tokyo.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology; D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003872:Dermatitis / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology*; D007093:Imidazoles / Q000008:administration & dosage; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D000072516:Retinoic Acid 4-Hydroxylase; D012867:Skin / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000276:immunology
chemical_list: D007093:Imidazoles; D058486:Receptors, Purinergic P2X7; D051195:Toll-Like Receptor 2; D014212:Tretinoin; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; C061121:liarozole