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The Enzyme Cyp26b1 Mediates Inhibition of Mast-Cell Activation by Fibroblasts to Maintain Skin-Barrier Homeostasis

Immunity http://dx.doi.org/10.1016/j.immuni.2014.01.014 (2014)
Yosuke Kurashima1–4, Takeaki Amiya1,2,4,5, Kumiko Fujisawa1,2, Naoko Shibata1,2,4,5, Yuji Suzuki1, Yuta Kogure1,4,5, Eri Hashimoto1,4, Atsushi Otsuka6, Kenji Kabashima6, Shintaro Sato1,2, Takeshi Sato1,4,5, Masato Kubo7,8, Shizuo Akira9, Kensuke Miyake3, Jun Kunisawa1,2,4,5,10,11, and Hiroshi Kiyono1,2,5,10
1. Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan 2. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan 3. Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan 4. Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan 5. Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8561, Japan 6. Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan 7. Laboratory for Cytokine Regulation, Research Center for Integrative Medical Science, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan 8. 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. International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan 11. Department of Microbiology and Immunology, Kobe University School of Medicine, Kobe 650-0017, Japan

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.