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The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.


Kojiro Tsujihana, Kosuke Tanegashima, Yasuko Santo, Hiroyuki Yamada, Sota Akazawa, Ryuta Nakao, Keiko Tominaga, Risa Saito, Yasumasa Nishito, Ryu-Ichiro Hata, Tomonori Nakamura, Iori Murai, Yuka Kono, Maho Sugawa, Miki Tanioka, Gyohei Egawa, Masao Doi, Tadashi Isa, Kenji Kabashima, Takahiko Hara, Hitoshi Okamura. Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity. Proceedings of the National Academy of Sciences of the United States of America. 2022 Jun 21;119(25):e2116027119

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PMID: 35704759

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