A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.
Cell Metab
; 36(8): 1726-1744.e10, 2024 Aug 06.
Article
in En
| MEDLINE
| ID: mdl-38986617
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interleukins
/
Th17 Cells
/
Interleukin-22
/
Glutathione
/
Mitochondria
Limits:
Animals
Language:
En
Journal:
Cell Metab
Journal subject:
METABOLISMO
Year:
2024
Document type:
Article