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

•Skin mast cells express no or low P2X7•Skin fibroblasts inhibit P2X7 expression on mast cells by degrading retinoic acid•Imbalanced retinoic acid metabolism induces mast cell- and P2X7-dependent dermatitis•Skin microbiota mediates TLR2-dependent production of P2X7 ligands

SummaryMast 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.

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