ArticleImmunity2023
Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.
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Article in Immunity, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 75 citations in OpenAlex.
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Authors and funding
34 authors at 11 institutions in 6 countries.
Jinzhi DuanDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Juan D MatuteDivision 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.
Lukas W UngerCambridge 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.
Thomas HanleyDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Alexandra SchnellEvergrande 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.
Xi LinDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Niklas KrupkaDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Paul GriebelDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Conner LambdenEvergrande 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.
Brandon SitDivision of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
Joep GrootjansDepartment of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, Location AMC, 1105 AZ Amsterdam, The Netherlands.
Michal PyzikDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Felix SommerInstitute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany.
Sina KaiserInstitute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany.
Maren Falk-PaulsenInstitute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany.
Helmut GrasbergerDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
John Y KaoDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Tobias FuhrerInstitute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zürich, Zürich, Switzerland.
Hai LiDepartment of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
Donggi PaikDepartment of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Yunjin LeeDepartment of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Samuel RefetoffDepartment of Medicine, Pediatrics and Committee on Genetics, The University of Chicago, Chicago, IL 60637, USA.
Jonathan N GlickmanDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Adrienne W PatonResearch Centre for Infectious Diseases, Department of Molecular and Biomedical Science, the University of Adelaide, Adelaide, 5005, Australia.
Lynn BryMassachusetts Host-Microbiome Center, Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
James C PatonResearch Centre for Infectious Diseases, Department of Molecular and Biomedical Science, the University of Adelaide, Adelaide, 5005, Australia.
Uwe SauerInstitute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zürich, Zürich, Switzerland.
Andrew J MacphersonDepartment of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
Philip RosenstielInstitute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany.
Vijay K KuchrooEvergrande 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.
Matthew K WaldorDivision of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA.
Jun R HuhDepartment of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Arthur KaserCambridge 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.
Richard S BlumbergDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rblumberg@bwh.harvard.edu.
Brigham and Women's Hospital · USBroad Institute · USHarvard University · USETH Zurich · CHMichigan Medicine · USThe University of Adelaide · AUUniversity of Bern · CHUniversity of Cambridge · GBAmsterdam University Medical Centers · NLBeth Israel Deaconess Medical Center · USUniversity of Chicago · US
Funding
Pediatric Scientist Development Program (PSDP) [K12]K12HD000850 · NICHD · YALE UNIVERSITY · PI Sallie R. Permar · 1987 to 2026
$44.1MSTRUCTURE-FUNCTION RELATIONSHIPS IN THE ALIMENTARY TRACTP30DK034854 · NIDDK · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JONATHAN C KAGAN · 1986 to 2026
$32.4MPilot and Feasibility ProgramP30DK020595 · NIDDK · UNIVERSITY OF CHICAGO · PI Raghavendra G Mirmira · 2013 to 2026
$20.9MRegulation of Mucosal LymphocytesR01DK051362 · NIDDK · BRIGHAM AND WOMEN'S HOSPITAL · PI Richard S Blumberg, Yu-Hwa Huang Blumberg · 1997 to 2026
$13.5MINTESTINAL TRANSCYTOSIS OF IGG IN ADULT LIFER01DK053056 · NIDDK · BRIGHAM AND WOMEN'S HOSPITAL · PI BLUMBERG, RICHARD S · 1997 to 2021
$10.6MMOLECULAR CHARACTERIZATION OF MUCOSAL LYMPHOCYTESR01DK044319 · NIDDK · BRIGHAM AND WOMEN'S HOSPITAL · PI Richard S Blumberg · 1992 to 2026
$10.4MEndoplasmic reticulum stress and intestinal inflammationR01DK088199 · NIDDK · BRIGHAM AND WOMEN'S HOSPITAL · PI Richard S Blumberg · 2010 to 2026
$9.6MTHYROID PHYSIOLOGY STUDIES OF INHERITED DISORDERSR01DK015070 · NIDDK · UNIVERSITY OF CHICAGO · PI ANTONIO C BIANCO, Alexandra Mihaela Dumitrescu · 1986 to 2026
$8.1MVibrio cholerae intestinal colonization and vaccine developmentR01AI042347 · NIAID · TUFTS UNIVERSITY BOSTON · PI WALDOR, MATTHEW K · 1998 to 2025
$7.3MCharacterization of Mucosal LymphocytesR37DK044319 · NIDDK · BRIGHAM AND WOMEN'S HOSPITAL · PI BLUMBERG, RICHARD S · 2005 to 2014
$7.2MTHYROID PHYSIOLOGY STUDIES OF INHERITED DISORDERSR37DK015070 · NIDDK · UNIVERSITY OF CHICAGO · PI REFETOFF, SAMUEL · 1989 to 2015
$5.6MBacterial metabolites controlling Th17 cellsR01DK110559 · NIDDK · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI HUH, JUN R. · 2016 to 2024
$5.1MNIAID NIH HHS R01 AI042347NIAID NIH HHS R01 AI169075NICHD NIH HHS K12 HD000850NIDDK NIH HHS P30 DK020595NIDDK NIH HHS P30 DK034854NIDDK NIH HHS R01 DK015070NIDDK NIH HHS R01 DK044319NIDDK NIH HHS R01 DK051362NIDDK NIH HHS R01 DK053056NIDDK NIH HHS R01 DK088199NIDDK NIH HHS R01 DK110559NIDDK NIH HHS R01 DK117565NIDDK NIH HHS R37 DK015070NIDDK NIH HHS R37 DK044319NIDDK NIH HHS R56 DK053056Wellcome TrustWellcome Trust 106260/Z/14/ZWellcome Trust 222497/Z/21/Z
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.
Indexed as
Endoplasmic Reticulum StressIntestinal MucosaTh17 CellsAnimalsAnti-Bacterial AgentsCell DifferentiationHumansMiceMice, TransgenicPurinesAnti-Bacterial AgentspurinePurinesCitrobacter rodentiumcommensal bacterialepithelial endoplasmic reticulum stressinflammatory bowel diseasepurine metabolismROS signalsTH17 cells
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