The IRE1α/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease

• Published in: The Journal of clinical investigation Vol. 134; no. 13; pp. 1 - 16
• Main Authors: Cao, Siyan, Fachi, Jose Luis, Ma, Kaiming, Ulezko Antonova, Alina, Wang, Qianli, Cai, Zhangying, Kaufman, Randal J, Ciorba, Matthew A, Deepak, Parakkal, Colonna, Marco
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2024
• Subjects: Animal models; Biomarkers; Cell culture; Cellular stress response; Circadian rhythm; Colitis; Crohn's disease; Crohns disease; Croup; Cytokines; Homeostasis; Inflammatory bowel disease; Inflammatory bowel diseases; Inositol; Interleukin 23; Intestine; Kinases; Lymphoid cells; Neuropeptides; Proteins; Transcription factors; Inflammatory bowel disease; Innate immunity; Immunology; Cell stress; Gastroenterology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI174198

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.