Intrinsic STING Switches off Pathogenetic Programs of Th1 Cells to Inhibit Colitis.
Intrinsic STING Switches off Pathogenetic Programs of Th1 Cells to Inhibit Colitis.
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DOI：
10.1016/j.jcmgh.2023.01.010
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发表时间：
2023
影响因子：
7.2
通讯作者：
Cong, Yingzi
中科院分区：
文献类型：
--
作者：
Yang, Wenjing;Yu, Tianming;Zhou, Guangxi;Yao, Suxia;Wakamiya, Maki;Hu, Haitao;Paessler, Slobodan;Sun, Jiaren;Cong, Yingzi
T辅助1（Th 1）效应细胞与炎症性肠病有关。干扰素基因刺激物（STING）是一种细胞内DNA传感器，已被证明可以调节感染和各种癌症。然而，Th 1细胞中的内在STING信号是否以及如何调节结肠炎仍然是未知的。使用葡聚糖硫酸钠诱导的结肠炎和野生型/STING缺陷型CD 4 +T细胞过继转移模型来分析STING在调节结肠炎中的作用。通过流式细胞术、RNA测序、代谢测定和线粒体功能来确定STING对Th 1细胞的影响。16 S核糖体RNA测序和无菌小鼠被用来研究微生物群是否参与其中。测定STING激动剂在鼠结肠炎中的体内作用。还测定了STING在人T细胞中的表达和作用。STING的激活将促炎性IFNγ+ Th 1细胞转化为IL-10+IFNγ+ Th 1细胞，其在诱导结肠炎中的致病性显著降低。STING通过诱导STAT 3转位到细胞核和线粒体中，分别促进Blimp 1表达和线粒体氧化，从而促进Th 1细胞产生IL-10。阻断葡萄糖或谷氨酰胺衍生的氧化，而不是脂质衍生的氧化，抑制IL-10的STING诱导。STING-/-小鼠的肠道微生物群发生了变化，但改变的微生物群并不介导STING对肠道CD 4 +T细胞产生IL-10的影响。翻译，STING激动剂抑制急性和慢性结肠炎。肠STING+ CD 4 +T细胞在炎性肠病患者中增加，并且STING激动剂上调人CD 4 +T细胞中的IL-10产生。这些发现确立了T细胞内在STING在关闭肠道炎症中Th 1细胞致病程序中的关键作用。
T helper 1 (Th1) effector cells are implicated in inflammatory bowel disease. The stimulator of interferon genes (STING), an intracellular DNA sensor, has been shown to regulate infection and various cancers. However, whether and how intrinsic STING signaling in Th1 cells regulates colitis is still unknown. Dextran sodium sulfate–induced colitis and wild-type/STING-deficient CD4+T cell adoptive transfer models were used to analyze the role of STING in regulating colitis. The effect of STING on Th1 cells was determined by flow cytometry, RNA sequencing, metabolic assays, and mitochondrial functions. 16S ribosomal RNA sequencing and germ-free mice were used to investigate whether the microbiota were involved. The in vivo effect of STING agonist in murine colitis was determined. The expression and role of STING in human T cells were also determined. Activation of STING transformed proinflammatory IFNγ+Th1 cells into IL-10+IFNγ+Th1 cells, which were dramatically less pathogenic in inducing colitis. STING promoted Th1 interleukin (IL)-10 production by inducing STAT3 translocation into nuclear and mitochondria, which promoted Blimp1 expression and mitochondrial oxidation, respectively. Blockade of glucose or glutamine-derived oxidation, but not lipid-derived oxidation, suppressed STING induction of IL-10. Gut microbiota were changed in STING–/– mice, but the altered microbiota did not mediate STING effects on intestinal CD4+T cell production of IL-10. Translationally, STING agonists suppressed both acute and chronic colitis. Intestinal STING+ CD4+T cells were increased in inflammatory bowel disease patients, and STING agonists upregulated IL-10 production in human CD4+T cells. These findings establish a crucial role of T cell–intrinsic STING in switching off the pathogenic programs of Th1 cells in intestinal inflammation.
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影响因子：
14.9
作者：
Klindworth A;Pruesse E;Schweer T;Peplies J;Quast C;Horn M;Glöckner FO
通讯作者：
Glöckner FO
影响因子：
7.3
作者：
Kubo M;Motomura Y
通讯作者：
Motomura Y
影响因子：
8.8
作者：
Ahn J;Son S;Oliveira SC;Barber GN
通讯作者：
Barber GN
影响因子：
7.3
作者：
Okude H;Ori D;Kawai T
通讯作者：
Kawai T
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
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作者：
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