Ye Yulan, Liu Changqin, Wu Ruijin, Kang Dengfeng, Gao Han, Lv Huiying, Feng Zhongsheng, Shi Yanhong, Liu Zhanju, Chen Liang
Center for IBD Research and Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China; Department of Gastroenterology, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou 215008, China.
Center for IBD Research and Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Mucosal Immunol. 2024 Dec;17(6):1161-1173. doi: 10.1016/j.mucimm.2024.07.010. Epub 2024 Aug 5.
Period circadian clock 2 (PER2) is involved in the pathogenesis of various inflammatory and autoimmune diseases. However, there are gaps in our understanding of the role of PER2 in regulating CD4 T cells beyond its time-keeping function in ulcerative colitis (UC) pathogenesis. Our findings revealed PER2 was predominantly expressed in CD4 T cells, while it was significantly decreased in the inflamed mucosa and peripheral blood CD4 T cells of UC patients compared with that in Crohn's disease (CD) patients and healthy controls (HC). Notably, PER2 expression was significantly recovered in UC patients in remission (R-UC) compared to that in active UC patients (A-UC) but not in CD patients. It was negatively correlated with the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Crohn's Disease Activity Index (CDAI), Simple Endoscopic Score for Crohn's disease (SES-CD), and C-reactive protein (CRP), respectively. Overexpression of PER2 markedly inhibited IFN-γ production in UC CD4 T cells. RNA-seq analysis showed that overexpression of PER2 could repress the expression of a disintegrin and metalloproteinase 12 (ADAM12), a costimulatory molecule that determines Th1 cell fate. Mechanistically, cleavage under targets and tagmentation (CUT&Tag) analysis revealed that PER2 down-regulated ADAM12 expression by reducing its binding activity, thereby suppressing IFN-γ production in UC CD4 T cells. Additionally, our data further demonstrated that ADAM12 was upregulated in CD4 T cells and inflamed mucosa of A-UC patients compared to HC. Our study reveals a critical role of PER2 in regulating CD4 T cell differentiation and highlights its potential as a therapeutic target for UC treatment.
周期生物钟2（PER2）参与多种炎症性和自身免疫性疾病的发病机制。然而，除了其在溃疡性结肠炎（UC）发病机制中的计时功能外，我们对PER2在调节CD4 T细胞中的作用的理解仍存在空白。我们的研究结果显示，PER2主要在CD4 T细胞中表达，而与克罗恩病（CD）患者和健康对照（HC）相比，UC患者炎症黏膜和外周血CD4 T细胞中的PER2表达显著降低。值得注意的是，与活动期UC患者（A-UC）相比，缓解期UC患者（R-UC）的PER2表达显著恢复，但CD患者没有。它分别与溃疡性结肠炎内镜严重程度指数（UCEIS）、克罗恩病活动指数（CDAI）、克罗恩病简易内镜评分（SES-CD）和C反应蛋白（CRP）呈负相关。PER2的过表达显著抑制UC CD4 T细胞中IFN-γ的产生。RNA测序分析表明，PER2的过表达可抑制去整合素和金属蛋白酶12（ADAM12）的表达，ADAM12是一种决定Th1细胞命运的共刺激分子。机制上，靶点切割与标签化（CUT&Tag）分析显示，PER2通过降低其结合活性下调ADAM12表达，从而抑制UC CD4 T细胞中IFN-γ的产生。此外，我们的数据进一步证明，与HC相比，A-UC患者的CD4 T细胞和炎症黏膜中ADAM12上调。我们的研究揭示了PER2在调节CD4 T细胞分化中的关键作用，并突出了其作为UC治疗靶点的潜力。
