期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 135, 期 12, 页码 3001-3008出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/jid.2015.316
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资金
- Ministry of Education, Culture, Sports, Science, and Technology, Japan
- Grants-in-Aid for Scientific Research [15K19573, 15H04864, 26670475] Funding Source: KAKEN
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 gamma/delta(+) T cells, respectively. In addition, CLOCK directly bound to the promoter of IL-23R in gamma/delta(+) 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 gamma/delta(+) T cells, establishing a mechanistic link between psoriasis and the circadian clock.
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