Fitness
A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation – PubMed
. 2024 Jul 3:S1550-4131(24)00235-3.
doi: 10.1016/j.cmet.2024.06.010.
Online ahead of print.
Affiliations
Item in Clipboard
Cell Metab.
.
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.
Keywords:
C. rodentium; Gclc; IL-22; ROS; T cells; Th17 cells; colitis; gastrointestinal infection; glutathione; intestinal barrier; mitochondrial function.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests The authors declare no competing interests.
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