1. The IRE1[alpha]/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease
- Author
-
Cao, Siyan, Fachi, Jose L., Ma, Kaiming, Antonova, Alina Ulezko, Wang, Qianli, Cai, Zhangying, Kaufman, Randal J., Ciorba, Matthew A., Deepak, Parakkal, and Colonna, Marco
- Subjects
Cytokines -- Analysis ,Inflammatory bowel diseases -- Diagnosis -- Care and treatment ,Inositol -- Dosage and administration ,Disease susceptibility -- Analysis ,Health care industry ,Diagnosis ,Care and treatment ,Analysis ,Dosage and administration - Abstract
Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. ER stress is linked to inflammatory bowel disease (IBD). Here, we used cell culture, mouse models, and human specimens to determine whether ER stress in ILC3s affects IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24-hour rhythmic expression pattern of the master ER stress response regulator inositol-requiring kinase 1[alpha]/X-box-binding protein 1 (IRE1[alpha]/XBP1). Proinflammatory cytokine IL-23 selectively stimulated IRE1[alpha]/XBP1 in mouse ILC3s through mitochondrial ROS (mtROS). IRE1[alpha]/XBP1 was activated in ILC3s from mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1[alpha] deletion in ILC3s ([Ire1[alpha].sup.[DELTA]Rorc]) showed reduced expression of the 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.sup.+] ILC3s in patients with Crohn's disease before administration of ustekinumab, an anti-IL-12/IL- 23 antibody, positively correlated with the response to treatment. We demonstrate that a noncanonical mtROS-IRE1[alpha]/XBP1 pathway augmented cytokine production by ILC3s and identify [XBP1s.sup.+] ILC3s as a potential biomarker for predicting the response to anti-IL-23 therapies in IBD., Introduction Innate lymphoid cells (ILCs) are a group of immune cells that exhibit lymphoid characteristics yet lack antigen-specific receptors found on T and B cells (1). Group 3 ILCs (ILC3s) [...]
- Published
- 2024
- Full Text
- View/download PDF