TY - JOUR
T1 - A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation
AU - Bonetti, Lynn
AU - Horkova, Veronika
AU - Grusdat, Melanie
AU - Longworth, Joseph
AU - Guerra, Luana
AU - Kurniawan, Henry
AU - Franchina, Davide G.
AU - Soriano-Baguet, Leticia
AU - Binsfeld, Carole
AU - Verschueren, Charlène
AU - Spath, Sabine
AU - Ewen, Anouk
AU - Koncina, Eric
AU - Gérardy, Jean Jacques
AU - Kobayashi, Takumi
AU - Dostert, Catherine
AU - Farinelle, Sophie
AU - Härm, Janika
AU - Fan, Yu Tong
AU - Chen, Ying
AU - Harris, Isaac S.
AU - Lang, Philipp A.
AU - Vasiliou, Vasilis
AU - Waisman, Ari
AU - Letellier, Elisabeth
AU - Becher, Burkhard
AU - Mittelbronn, Michel
AU - Brenner, Dirk
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/8/6
Y1 - 2024/8/6
N2 - 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.
AB - 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.
KW - C. rodentium
KW - colitis
KW - gastrointestinal infection
KW - Gclc
KW - glutathione
KW - IL-22
KW - intestinal barrier
KW - mitochondrial function
KW - ROS
KW - T cells
KW - Th17 cells
UR - http://www.scopus.com/inward/record.url?scp=85198596226&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/38986617/
U2 - 10.1016/j.cmet.2024.06.010
DO - 10.1016/j.cmet.2024.06.010
M3 - Article
C2 - 38986617
AN - SCOPUS:85198596226
SN - 1550-4131
VL - 36
SP - 1726-1744.e10
JO - Cell Metabolism
JF - Cell Metabolism
IS - 8
ER -