Circadian Gene Clock Regulates Psoriasis-Like Skin Inflammation in Mice

• Published in: Journal of investigative dermatology Vol. 135; no. 12; pp. 3001 - 3008
• Main Authors: Ando, Noriko, Nakamura, Yuki, Aoki, Rui, Ishimaru, Kayoko, Ogawa, Hideoki, Okumura, Ko, Shibata, Shigenobu, Shimada, Shinji, Nakao, Atsuhito
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2015; Elsevier Limited; Nature Publishing Group
• Subjects: Aminoquinolines - pharmacology; Animals; Circadian Rhythm; CLOCK Proteins - genetics; CLOCK Proteins - physiology; Dermatitis - etiology; Dermatitis - genetics; Dermatitis - immunology; Female; Interleukin-23 - physiology; Mice; Mice, Inbred C57BL; Mutation; Original; Period Circadian Proteins - genetics; Psoriasis - etiology; Psoriasis - genetics; Psoriasis - immunology; Receptors, Antigen, T-Cell, gamma-delta - analysis; T-Lymphocytes - immunology
• DOI: 10.1038/jid.2015.316
• ISSN: 0022-202X; 1523-1747

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.