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J Invest Dermatol. 2015 Dec;135(12):3001-3008. doi: 10.1038/jid.2015.316. Epub 2015 Aug 20.

Circadian Gene Clock Regulates Psoriasis-Like Skin Inflammation in Mice.

Author information

1
Department of Dermatology, University of Yamanashi, Faculty of Medicine, Yamanashi, Chuo, Japan.
2
Department of Immunology, University of Yamanashi, Faculty of Medicine, Yamanashi, Chuo, Japan.
3
Atopy Research Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
4
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan.
5
Department of Immunology, University of Yamanashi, Faculty of Medicine, Yamanashi, Chuo, Japan; Atopy Research Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. Electronic address: anakao@yamanashi.ac.jp.

Abstract

There are several reports suggesting that the pathophysiology of psoriasis may be associated with aberrant circadian rhythms. However, the mechanistic link between psoriasis and the circadian time-keeping system, "the circadian clock," remains unclear. This study determined whether the core circadian gene, Clock, had a regulatory role in the development of psoriasis. For this purpose, we compared the development of psoriasis-like skin inflammation induced by the Toll-like receptor 7 ligand imiquimod (IMQ) between wild-type mice and mice with a loss-of-function mutation of Clock. We also compared the development of IMQ-induced dermatitis between wild-type mice and mice with a loss-of-function mutation of Period2 (Per2), another key circadian gene that inhibits CLOCK activity. We found that Clock mutation ameliorated IMQ-induced dermatitis, whereas the Per2 mutation exaggerated IMQ-induced dermatitis, when compared with wild-type mice associated with decreased or increased IL-23 receptor (IL-23R) expression in γ/δ+ T cells, respectively. In addition, CLOCK directly bound to the promoter of IL-23R in γ/δ+ T cells, and IL-23R expression in the mouse skin was under circadian control. These findings suggest that Clock is a novel regulator of psoriasis-like skin inflammation in mice via direct modulation of IL-23R expression in γ/δ+ T cells, establishing a mechanistic link between psoriasis and the circadian clock.

PMID:
26291684
PMCID:
PMC4653315
DOI:
10.1038/jid.2015.316
[Indexed for MEDLINE]
Free PMC Article

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