2. Academic Validation
  3. Xbp1 controls the reparative function of intestinal ILC2s during colitis

Xbp1 controls the reparative function of intestinal ILC2s during colitis

  • J Exp Med. 2026 Jan 5;223(1):e20250440. doi: 10.1084/jem.20250440.
Yanyan Cui # 1,  Zixiao Zhao # 2,  Jing Shen # 1,  Yatai Chen # 1,  Qiuheng Tian # 1,  Yang Liu 1,  Yunjiao Zhai 1,  Bowen Xu 3,  Jiajie Hou 4 5,  Chunyang Li 6,  Yanbo Yu 1 7,  Xiaohuan Guo 8 9,  Ju Qiu 10,  Detian Yuan 3,  Shiyang Li 1 7 11
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Qilu Hospital of Shandong University, Advanced Medical Research Institute, Shandong University, Jinan, China.
  • 2 Department of Digestive Endoscopy, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China.
  • 4 Faculty of Health Sciences, Cancer Centre, University of Macau, Macau, China.
  • 5 MOE Frontier Science Centre for Precision Oncology, University of Macau , Macau, China.
  • 6 Key Laboratory for Experimental Teratology of Ministry of Education and Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 7 Shandong Provincial Clinical Research Center for Digestive Diseases , Jinan, China.
  • 8 Institute for Immunology, School of Medicine, Tsinghua University , Beijing, China.
  • 9 Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.
  • 10 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 11 Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, China.
  • # Contributed equally.
PMID: 41165618 DOI: 10.1084/jem.20250440
Abstract

Ulcerative colitis (UC) is primarily characterized by inflammation-induced tissue damage, but impaired tissue repair also drives disease progression. This study demonstrates group 2 innate lymphoid cells (ILC2s), key players in tissue repair, are dysfunctional in UC and experimental colitis due to disrupted endoplasmic reticulum protein processing. We show that the pro-repair function of gut ILC2s depends on the IRE1α-Xbp1 branch of unfolded protein response (UPR), supported by IL-25 and suppressed by interferon-γ (IFN-γ). During colitis, loss of IL-25 and rise of IFN-γ hinder Xbp1 mRNA splicing, weakening ILC2s' ability to mediate tissue repair. Mechanistically, spliced Xbp1 drives folate-dependent one-carbon (1C) metabolism by promoting dihydrofolate reductase expression. Translationally, the 1C metabolite adenosine 5'-monophosphate alleviated colitis in both ILC2-specific Xbp1 knockout and wild-type mice. Our findings highlight the UPR's role in sensing gut environment to regulate ILC2 function and suggest folate-mediated 1C metabolism as a potential target for UC therapy.

Figures
Products
Inhibitors & Agonists
Other Products