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
  • 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.

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