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  3. Chronic psychological stress-orchestrated glial-ILC3 circuit exacerbates intestinal inflammation and depression

Chronic psychological stress-orchestrated glial-ILC3 circuit exacerbates intestinal inflammation and depression

  • Brain Behav Immun. 2025 Sep 21:130:106118. doi: 10.1016/j.bbi.2025.106118.
Zhencui Zhang 1,  Shouyang Ren 1,  Xinyi Fan 1,  Huiying Chen 2,  Jiaheng Chen 1,  Xiaoqian Wang 1,  Han Zong 1,  Shengshuai Zhang 1,  Tianyi Zhao 1,  Yujie Sun 3,  Ruixin Pang 3,  Wengang Song 4,  Wen Zhang 3,  Ben Wang 5,  Zhengtao Chen 6,  Li Ge 7
Affiliations

Affiliations

  • 1 School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province 250117, China.
  • 2 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province 250021, China.
  • 3 School of Laboratory Animal & Shandong Laboratory Animal Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province 250117, China.
  • 4 Shandong Province University Clinical Immunology Translational Medicine Laboratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China.
  • 5 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province 250021, China. Electronic address: wangben@bjmu.edu.cn.
  • 6 School of Laboratory Animal & Shandong Laboratory Animal Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province 250117, China. Electronic address: cztd_666@163.com.
  • 7 Department of Gastroenterology, The Second Affiliated Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000 Shandong, China. Electronic address: juliagl@126.com.
PMID: 40987409 DOI: 10.1016/j.bbi.2025.106118
Abstract

Chronic psychological stress can exacerbate intestinal inflammation both in patients with inflammatory bowel disease (IBD) and animal models of experimental colitis, but the underlying mechanism remains poorly understood. Here, we identified a chronic stress-orchestrated intestinal glia-Group 3 innate lymphoid cell (ILC3) circuit that impairs innate interleukin (IL)-22-mediated immune protection. We found that stress promoted the release of excessive amounts of glucocorticoid (GC) by the adrenal cortex through activation of the hypothalamic-pituitary-adrenal axis. Subsequently, chronically elevated level of GC dysregulated the phenotype and function of enteric glial cells (EGCs) through binding to the Glucocorticoid Receptor on EGCs, thereby weakening glial-derived neurotrophic factor production. These lead to the deficiency of innate IL-22 and impairment of gut defense. Simultaneously, we demonstrated that exacerbation of intestinal inflammation further unleashes the progression of neuroinflammation and anxiety/depression-like behaviors. Our work sheds light on a novel mechanism by which chronic psychological stress exacerbates intestinal inflammation, expanding the understanding of ILC3 biology and ILC3-mediated mucosal immunity. We proposed an innate IL-22-based therapeutic strategy for IBD patients with psychological comorbidities, and suggested stress management as a valuable component of IBD care in the context of bidirectional brain-gut communication.

Keywords

Chronic psychological stress; Colitis; Enteric glial cells; Group 3 innate lymphoid cells; Interleukin-22.

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