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

TitleIL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions.
Publication TypeJournal Article
Year of Publication2015
AuthorsMonticelli LA, Osborne LC, Noti M, Tran SV, Zaiss DMW, Artis D
JournalProc Natl Acad Sci U S A
Volume112
Issue34
Pagination10762-7
Date Published2015 Aug 25
ISSN1091-6490
KeywordsAnimals, Colitis, Dextran Sulfate, Disease Models, Animal, EGF Family of Proteins, Epithelium, Feedback, Physiological, Immunity, Innate, Immunity, Mucosal, Immunotherapy, Adoptive, Interleukin-33, Intestinal Mucosa, Lung, Lymphocytes, Mice, Mice, Knockout, Mucins, Peyer's Patches, Receptor, Epidermal Growth Factor, Recombinant Proteins, RNA, Messenger, Signal Transduction, Specific Pathogen-Free Organisms
Abstract

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.

DOI10.1073/pnas.1509070112
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID26243875
PubMed Central IDPMC4553775
Grant List095831 / / Wellcome Trust / United Kingdom
AI061570 / AI / NIAID NIH HHS / United States
AI074878 / AI / NIAID NIH HHS / United States
AI087990 / AI / NIAID NIH HHS / United States
AI095466 / AI / NIAID NIH HHS / United States
AI095608 / AI / NIAID NIH HHS / United States
AI097333 / AI / NIAID NIH HHS / United States
AI102942 / AI / NIAID NIH HHS / United States
AI106697 / AI / NIAID NIH HHS / United States
T32AI007532 / AI / NIAID NIH HHS / United States