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

Jinzhi Duan; Juan D Matute; Lukas W Unger; Thomas Hanley; Alexandra Schnell; Xi Lin; Niklas Krupka; Paul Griebel; Conner Lambden; Brandon Sit; Joep Grootjans; Michal Pyzik; Felix Sommer; Sina Kaiser; Maren Falk-Paulsen; Helmut Grasberger; John Y Kao; Tobias Fuhrer; Hai Li; Donggi Paik; Yunjin Lee; Samuel Refetoff; Jonathan N Glickman; Adrienne W Paton; Lynn Bry; James C Paton; Uwe Sauer; Andrew J Macpherson; Philip Rosenstiel; Vijay K Kuchroo; Matthew K Waldor; Jun R Huh; Arthur Kaser; Richard S Blumberg

doi:10.1016/j.immuni.2023.02.018

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

Immunity. 2023 May 9;56(5):1115-1131.e9. doi: 10.1016/j.immuni.2023.02.018. Epub 2023 Mar 13.

Authors

Jinzhi Duan¹, Juan D Matute², Lukas W Unger³, Thomas Hanley¹, Alexandra Schnell⁴, Xi Lin¹, Niklas Krupka¹, Paul Griebel¹, Conner Lambden⁴, Brandon Sit⁵, Joep Grootjans⁶, Michal Pyzik¹, Felix Sommer⁷, Sina Kaiser⁷, Maren Falk-Paulsen⁷, Helmut Grasberger⁸, John Y Kao⁸, Tobias Fuhrer⁹, Hai Li¹⁰, Donggi Paik¹¹, Yunjin Lee¹¹, Samuel Refetoff¹², Jonathan N Glickman¹³, Adrienne W Paton¹⁴, Lynn Bry¹⁵, James C Paton¹⁴, Uwe Sauer⁹, Andrew J Macpherson¹⁰, Philip Rosenstiel⁷, Vijay K Kuchroo⁴, Matthew K Waldor¹⁶, Jun R Huh¹¹, Arthur Kaser¹⁷, Richard S Blumberg¹⁸

Affiliations

¹ Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
³ Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, and Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, CB2 0AW, UK; Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, 10090, Austria.
⁴ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
⁵ Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁶ Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, Location AMC, 1105 AZ Amsterdam, The Netherlands.
⁷ Institute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany.
⁸ Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁹ Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zürich, Zürich, Switzerland.
¹⁰ Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
¹¹ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Medicine, Pediatrics and Committee on Genetics, The University of Chicago, Chicago, IL 60637, USA.
¹³ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹⁴ Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, the University of Adelaide, Adelaide, 5005, Australia.
¹⁵ Massachusetts Host-Microbiome Center, Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁶ Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA.
¹⁷ Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, and Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, CB2 0AW, UK.
¹⁸ Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rblumberg@bwh.harvard.edu.

PMID: 36917985
PMCID: PMC10175221 (available on 2024-05-09)
DOI: 10.1016/j.immuni.2023.02.018

Abstract

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.

Keywords: Citrobacter rodentium; ROS signals; TH17 cells; commensal bacterial; epithelial endoplasmic reticulum stress; inflammatory bowel disease; purine metabolism.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
Cell Differentiation
Endoplasmic Reticulum Stress* / drug effects
Humans
Intestinal Mucosa* / drug effects
Intestinal Mucosa* / metabolism
Mice
Mice, Transgenic
Th17 Cells* / cytology
Th17 Cells* / metabolism

Substances

purine
Anti-Bacterial Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding