Circadian Gene Clock Regulates Psoriasis-Like Skin Inflammation in Mice.
Circadian Gene Clock Regulates Psoriasis-Like Skin Inflammation in Mice.
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DOI：
10.1038/jid.2015.316
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
Nakao A
中科院分区：
文献类型：
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作者：
Ando N;Nakamura Y;Aoki R;Ishimaru K;Ogawa H;Okumura K;Shibata S;Shimada S;Nakao A
有几个报告表明银屑病的病理生理学可能与异常的昼夜节律有关。然而，银屑病和昼夜节律计时系统（“昼夜节律钟”）之间的机械联系仍不清楚。这项研究确定了核心昼夜节律基因Clock是否在银屑病的发展中具有调节作用。为此，我们比较了由Toll样受体7配体咪喹莫特（IMQ）诱导的野生型小鼠和Clock功能缺失突变小鼠之间银屑病样皮肤炎症的发展。我们还比较了野生型小鼠和Period 2（Per 2）功能缺失突变小鼠之间IMQ诱导的皮炎的发展，Period 2是另一个抑制CLOCK活性的关键昼夜节律基因。我们发现，与野生型小鼠相比，Clock突变改善了IMQ诱导的皮炎，而Per 2突变加重了IMQ诱导的皮炎，分别与γ/δ+ T细胞中IL-23受体（IL-23 R）表达的降低或增加相关。此外，CLOCK直接与γ/δ+ T细胞中IL-23 R的启动子结合，并且小鼠皮肤中IL-23 R的表达受昼夜节律控制。这些发现表明，Clock是小鼠银屑病样皮肤炎症的一种新型调节剂，通过直接调节γ/δ+ T细胞中的IL-23 R表达，建立了银屑病与昼夜节律钟之间的机制联系。
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.