Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut

• Published in: Immunity (Cambridge, Mass.) Vol. 56; no. 5; pp. 1115 - 1131.e9
• Main Authors: Duan, Jinzhi, Matute, Juan D., Unger, Lukas W., Hanley, Thomas, Schnell, Alexandra, Lin, Xi, Krupka, Niklas, Griebel, Paul, Lambden, Conner, Sit, Brandon, Grootjans, Joep, Pyzik, Michal, Sommer, Felix, Kaiser, Sina, Falk-Paulsen, Maren, Grasberger, Helmut, Kao, John Y., Fuhrer, Tobias, Li, Hai, Paik, Donggi, Lee, Yunjin, Refetoff, Samuel, Glickman, Jonathan N., Paton, Adrienne W., Bry, Lynn, Paton, James C., Sauer, Uwe, Macpherson, Andrew J., Rosenstiel, Philip, Kuchroo, Vijay K., Waldor, Matthew K., Huh, Jun R., Kaser, Arthur, Blumberg, Richard S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-05-2023
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Cell Differentiation; Citrobacter rodentium; commensal bacterial; Endoplasmic Reticulum Stress - drug effects; epithelial endoplasmic reticulum stress; Humans; inflammatory bowel disease; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Mice; Mice, Transgenic; purine metabolism; ROS signals; TH17 cells; Th17 Cells - cytology; Th17 Cells - metabolism; epithelial endoplasmic reticulum stress; purine metabolism; ROS signals; commensal bacterial; Citrobacter rodentium; TH17 cells; inflammatory bowel disease
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2023.02.018

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.
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•ER stress in intestinal epithelial cells (IEC) drives gut Th17 differentiation•Th17 cells induced by IEC-ER stress require H2O2 generated by DUOX2/DUOXA2•IEC-ROS induce Th17 differentiation through purine metabolites, including xanthine•IEC-ER stress drives microbial Th17 induction even under germ-free conditions
Intestinal epithelial cell (IEC)-adherent microbes are important for generation of intestinal Th17 cells. Duan et al. report that microbial adhesion drives IEC-ER stress and unfolded protein response (UPR). The UPR enhances IEC production of reactive oxygen species and purine metabolites that subsequently promote Th17 differentiation in the gut.