IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions Academic Article uri icon


MeSH Major

  • Colitis
  • EGF Family of Proteins
  • Immunity, Innate
  • Immunity, Mucosal
  • Interleukin-33
  • Lymphocytes
  • Receptor, Epidermal Growth Factor


  • The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33-dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG-epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.

publication date

  • August 25, 2015



  • Academic Article



  • eng

PubMed Central ID

  • PMC4553775

Digital Object Identifier (DOI)

  • 10.1073/pnas.1509070112

PubMed ID

  • 26243875

Additional Document Info

start page

  • 10762

end page

  • 7


  • 112


  • 34