Xbp1 controls the reparative function of intestinal ILC2s during colitis

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Ulcerative colitis (UC) involves inflammation-induced tissue damage and impaired repair.
• Group 2 innate lymphoid cells (ILC2s) are vital for tissue repair but are dysfunctional in UC.
• Endoplasmic reticulum stress and disrupted protein processing impact ILC2 function.

Purpose of the Study:

• To investigate the role of unfolded protein response (UPR) in gut ILC2 function during colitis.
• To elucidate the mechanisms by which UPR regulates ILC2-mediated tissue repair.
• To explore potential therapeutic targets for UC based on ILC2 function.

Main Methods:

• Analysis of ILC2s in UC and experimental colitis models.
• Assessment of the IRE1α-Xbp1 pathway within the UPR.
• Investigation of cytokine effects (IL-25, IFN-γ) on ILC2s.
• Measurement of folate-dependent one-carbon (1C) metabolism.
• Therapeutic intervention using 1C metabolites.

Main Results:

• Gut ILC2s' pro-repair function depends on the IRE1α-Xbp1 UPR pathway.
• Colitis disrupts this pathway via altered IL-25 and IFN-γ levels, impairing ILC2 repair capacity.
• Spliced Xbp1 promotes dihydrofolate reductase expression, driving 1C metabolism.
• Adenosine 5'-monophosphate, a 1C metabolite, ameliorated colitis in mouse models.

Conclusions:

• The UPR in gut ILC2s senses the gut environment to regulate tissue repair.
• Impaired UPR and subsequent metabolic dysfunction contribute to UC progression.
• Folate-mediated 1C metabolism represents a promising therapeutic target for UC.