IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin–EGFR interactions

Significance Mammalian barrier surfaces are exposed to environmental stimuli that can result in tissue damage. Interleukin (IL)-33–dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier sites, but the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s in the intestine remain poorly defined. Here we use a model of murine intestinal inflammation and reveal a previously unrecognized pathway of innate immune cell-mediated tissue protection in which IL-33 ameliorated disease through induction of ILC2s and the growth factor amphiregulin (AREG). Collectively, these data highlight a critical dialogue between damaged epithelia and innate immune cells and indicate that manipulation of the IL-33–ILC2–AREG pathway could provide therapeutic benefit in treatment of intestinal inflammatory diseases.