The enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis

Yosuke Kurashima; Takeaki Amiya; Kumiko Fujisawa; Naoko Shibata; Yuji Suzuki; Yuta Kogure; Eri Hashimoto; Atsushi Otsuka; Kenji Kabashima; Shintaro Sato; Takeshi Sato; Masato Kubo; Shizuo Akira; Kensuke Miyake; Jun Kunisawa; Hiroshi Kiyono

doi:10.1016/j.immuni.2014.01.014

The enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis

Immunity. 2014 Apr 17;40(4):530-41. doi: 10.1016/j.immuni.2014.01.014. Epub 2014 Apr 10.

Authors

Yosuke Kurashima¹, Takeaki Amiya², Kumiko Fujisawa³, Naoko Shibata², Yuji Suzuki⁴, Yuta Kogure⁵, Eri Hashimoto⁶, Atsushi Otsuka⁷, Kenji Kabashima⁷, Shintaro Sato³, Takeshi Sato⁵, Masato Kubo⁸, Shizuo Akira⁹, Kensuke Miyake¹⁰, Jun Kunisawa¹¹, Hiroshi Kiyono¹²

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁵ 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.
⁶ 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.
⁷ Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
⁸ 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.
⁹ Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
¹⁰ Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
¹¹ 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.
¹² 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.

PMID: 24726878
DOI: 10.1016/j.immuni.2014.01.014

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / immunology
Animals
Cell Degranulation / drug effects
Cell Degranulation / genetics
Cytochrome P-450 Enzyme System / genetics
Cytochrome P-450 Enzyme System / metabolism*
Dermatitis / immunology*
Fibroblasts / immunology*
Imidazoles / administration & dosage
Immunity, Innate / drug effects
Immunity, Innate / genetics
Mast Cells / drug effects
Mast Cells / immunology*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Microbiota / immunology
Receptors, Purinergic P2X7 / genetics
Receptors, Purinergic P2X7 / metabolism*
Retinoic Acid 4-Hydroxylase
Skin / immunology
Skin / metabolism*
Skin / microbiology
Toll-Like Receptor 2 / genetics
Toll-Like Receptor 2 / metabolism
Tretinoin / immunology

Substances

Imidazoles
Receptors, Purinergic P2X7
Toll-Like Receptor 2
Tretinoin
Adenosine Triphosphate
Cytochrome P-450 Enzyme System
Retinoic Acid 4-Hydroxylase
liarozole