昼夜节律钟成分 PER2 负向调节溃疡性结肠炎 CD4+ T 细胞 IFN-γ 的产生。

IF 7.9 2区 医学 Q1 IMMUNOLOGY
Yulan Ye, Changqin Liu, Ruijin Wu, Dengfeng Kang, Han Gao, Huiying Lv, Zhongsheng Feng, Yanhong Shi, Zhanju Liu, Liang Chen
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引用次数: 0

摘要

昼夜节律周期钟 2(PER2)参与了多种炎症和自身免疫性疾病的发病机制。然而,除了在溃疡性结肠炎(UC)发病机制中的计时功能外,我们对PER2在调控CD4+ T细胞中的作用的认识还存在差距。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)患者和健康对照组(HC)相比,PER2 在 UC 患者炎症粘膜和外周血 CD4+ T 细胞中的表达明显减少。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 表达明显恢复,但 CD 患者的 PER2 表达没有恢复。它分别与溃疡性结肠炎内镜下严重程度指数(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。过表达 PER2 能明显抑制 UC CD4+ T 细胞产生 IFN-γ。RNA-seq分析表明,过表达PER2可抑制崩解素和金属蛋白酶12(ADAM12)的表达,ADAM12是一种决定Th1细胞命运的成本刺激分子。从机理上讲,靶标下裂解和标记(CUT&Tag)分析表明,PER2 通过降低 ADAM12 的结合活性来下调其表达,从而抑制 UC CD4+ T 细胞中 IFN-γ 的产生。此外,我们的数据还进一步表明,与 HC 相比,A-UC 患者 CD4+ T 细胞和炎症粘膜中 ADAM12 表达上调。我们的研究揭示了 PER2 在调节 CD4+ T 细胞分化中的关键作用,并强调了其作为 UC 治疗靶点的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Circadian clock component PER2 negatively regulates CD4+ T cell IFN-γ production in ulcerative colitis.

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.

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来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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