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ResearchIn-Press PreviewGastroenterologyImmunology Open Access | 10.1172/JCI174198
1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
Find articles by Cao, S. in: JCI | PubMed | Google Scholar
1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
Find articles by Fachi, J. in: JCI | PubMed | Google Scholar
1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
Find articles by Ma, K. in: JCI | PubMed | Google Scholar
1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
Find articles by Ulezko Antonova, A. in: JCI | PubMed | Google Scholar
1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
Find articles by Wang, Q. in: JCI | PubMed | Google Scholar
1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
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1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
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1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
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1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
Find articles by Deepak, P. in: JCI | PubMed | Google Scholar
1Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America
3Degenerative Diseases Program, Center for Genetic Disorders and Aging Resea, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America
4Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States of America
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Published May 9, 2024 - More info
Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. Endoplasmic reticulum (ER) stress is linked to inflammatory bowel disease (IBD). Herein, we used cell culture, mouse models, and human specimens to examine if ER stress in ILC3s impacts IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24h-rhythmic expression pattern of the master ER stress response regulator, IRE1α/XBP1. Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial reactive oxygen species (mtROS). IRE1α/XBP1 was activated in ILC3s of mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in Crohn’s disease patients before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with response to treatment. We demonstrate that a non-canonical mtROS-IRE1α/XBP1 pathway augments cytokine production by ILC3s and identify XBP1s+ ILC3s as a potential biomarker for predicting response to anti-IL-23 therapies in IBD.