Xbp1 controls the reparative function of intestinal ILC2s during colitis
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.
Authors
- Yanbo Yu (ORCID: https://orcid.org/0000-0003-2995-3270)
- Bowen Xu (ORCID: https://orcid.org/0009-0005-9150-8145)
- Detian Yuan (ORCID: https://orcid.org/0000-0002-7247-4526)
- Xiaohuan Guo (ORCID: https://orcid.org/0000-0001-5152-3010)
- Ju Qiu (ORCID: https://orcid.org/0000-0002-1543-5678)
- Yunjiao Zhai (ORCID: https://orcid.org/0000-0002-3117-798X)
- Jiajie Hou (ORCID: https://orcid.org/0000-0002-9011-6837)
- Yang Liu (ORCID: https://orcid.org/0009-0007-1986-7025)
- Chunyang Li (ORCID: https://orcid.org/0000-0002-5798-2274)
- Shiyang Li (ORCID: https://orcid.org/0000-0003-1487-4991)
- Jing Shen (ORCID: https://orcid.org/0000-0003-1467-7699)
- Yanyan Cui (ORCID: https://orcid.org/0000-0003-2776-5284)
- Yatai Chen (ORCID: https://orcid.org/0009-0002-1469-4771)
- Zixiao Zhao (ORCID: https://orcid.org/0000-0002-6704-2892)
- Qiuheng Tian (ORCID: https://orcid.org/0009-0005-9853-0417)
Institutions
- Shandong University (CN)
- University of Macau (MO)
- University of Jinan (CN)
- National Clinical Research Center for Digestive Diseases (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Ministry of Education (ME)
- Ministry of Education (KR)
- Shandong Provincial Hospital (CN)
- Ministry of Education (PT)
- Shandong Provincial QianFoShan Hospital (CN)
- Qilu Hospital of Shandong University (CN)
- Shandong First Medical University (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1084/jem.20250440
- Citations
- 1
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.80