| Title: |
A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation. |
| Authors: |
Bonetti, Lynn; Horkova, Veronika; Longworth, Joseph; Guerra, Luana; Kurniawan, Henry; Franchina, Davide G; Soriano-Baguet, Leticia; Grusdat, Melanie; Spath, Sabine; Koncina, Eric; Ewen, Anouk; Binsfeld, Carole; Verschueren, Charlène; Gérardy, Jean-Jacques; Kobayashi, Takumi; Dostert, Catherine; Farinelle, Sophie; Härm, Janika; Chen, Ying; Harris, Isaac S; Lang, Philipp A; Vasiliou, Vasilis; Waisman, Ari; LETELLIER, Elisabeth; Becher, Burkhard; Mittelbronn, Michel; BRENNER, Dirk |
| Publication Year: |
2023 |
| Collection: |
University of Luxembourg: ORBilu - Open Repository and Bibliography |
| Subject Terms: |
Reactive oxygen species (ROS); Th17 cells; glutamate cysteine ligase (Gclc); glutathione; metabolism; Human health sciences; Immunology & infectious disease; Sciences de la santé humaine; Immunologie & maladie infectieuse |
| Description: |
Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc-deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection. |
| Document Type: |
report |
| Language: |
English |
| Relation: |
https://orbilu.uni.lu/handle/10993/58027; info:hdl:10993/58027; https://orbilu.uni.lu/bitstream/10993/58027/1/Bonetti%20L%20et%20al_bioRxiv_2023.07.06.547932v1.full.pdf; info:pmid:37489135 |
| DOI: |
10.1101/2023.07.06.547932 |
| Availability: |
https://orbilu.uni.lu/handle/10993/58027; https://orbilu.uni.lu/bitstream/10993/58027/1/Bonetti%20L%20et%20al_bioRxiv_2023.07.06.547932v1.full.pdf; https://doi.org/10.1101/2023.07.06.547932 |
| Rights: |
open access ; http://purl.org/coar/access_right/c_abf2 ; info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.F04536EB |
| Database: |
BASE |