卢森堡健康研究所Dirk Brenner团队近期取得重要工作进展，他们研究提出，Th17细胞固有谷胱甘肽/线粒体IL-22轴防止肠道炎症。相关研究成果2024年7月9日在线发表于《细胞—代谢》杂志上。

据介绍，肠道产生大量的活性氧（ROS），但T细胞抗氧化机制在维持肠道稳态中的作用尚不清楚。

研究人员使用T细胞特异性消融谷氨酸-半胱氨酸连接酶（Gclc）的催化亚基，该亚基损害谷胱甘肽（GSH）的产生，关键性地减少固有层中Th17细胞产生IL-22，这对肠道保护至关重要。在稳态条件下，Gclc缺乏不会改变细胞因子的分泌；然而，啮齿动物感染诱导ROS增加，并破坏线粒体功能和TFAM驱动的线粒体基因表达，导致细胞ATP减少。这些变化损害了PI3K/AKT/mTOR途径，减少了4E-BP1的磷酸化，从而限制了IL-22的翻译。由此产生的低IL-22水平导致细菌清除率低、严重的肠道损伤和高死亡率。

总之，这一研究结果强调了Th17细胞固有GSH在促进线粒体功能和IL-22蛋白合成的细胞信号传导中未被认识的重要作用，IL-22蛋白合成对肠道完整性和防御胃肠道感染至关重要。

附：英文原文

Title: A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation

Author: Lynn Bonetti, Veronika Horkova, Melanie Grusdat, Joseph Longworth, Luana Guerra, Henry Kurniawan, Davide G. Franchina, Leticia Soriano-Baguet, Carole Binsfeld, Charlène Verschueren, Sabine Spath, Anouk Ewen, Eric Koncina, Jean-Jacques Gérardy, Takumi Kobayashi, Catherine Dostert, Sophie Farinelle, Janika Hrm, Yu-Tong Fan, Ying Chen, Isaac S. Harris, Philipp A. Lang, Vasilis Vasiliou, Ari Waisman, Elisabeth Letellier, Burkhard Becher, Michel Mittelbronn, Dirk Brenner

Issue&Volume: 2024-07-09

Abstract: The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

DOI: 10.1016/j.cmet.2024.06.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00235-3