IL-1R1–dependent signaling coordinates epithelial regeneration in response to intestinal damage

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Science Immunology  07 May 2021:
Vol. 6, Issue 59, eabe8856
DOI: 10.1126/sciimmunol.abe8856

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Building back colonic crypts

Restoration of the colonic epithelium after mucosal injury depends on cell renewal initiated by intestinal stem cells (ISCs) and their progeny. Stromal cells near the base of colonic crypts secrete trophic factors for ISCs, but regulation of this process by proinflammatory mediators is not well understood. Cox et al. used mouse models of pathogen- or chemical-induced epithelial damage to investigate the contribution of IL-1 and its receptor (IL-1R1) to epithelial restitution. IL-1 release induced GREM1+ mesenchymal cells to produce R-spondin 3, a Wnt agonist supporting ISC renewal and proliferation. IL-1 also promoted innate lymphoid cell production of IL-22, a cytokine supporting colonocyte proliferation. These findings illustrate the need to consider the desirable regenerative properties of IL-1 when designing therapeutic approaches for chronic inflammatory diseases.


Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1+ mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from Citrobacter rodentium infection, IL-1R1–dependent RSPO3 production by GREM1+ mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium–induced colitis. These data demonstrate how IL-1R1–dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.

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