title: IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions.
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.
authors.affiliation: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10021;
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Monticelli
authors.affiliation: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10021;
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Osborne
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland;
authors.forename: Mario
authors.initials: M
authors.lastname: Noti
authors.affiliation: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10021;
authors.forename: Sara V
authors.initials: SV
authors.lastname: Tran
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, Scotland, United Kingdom.
authors.forename: Dietmar M W
authors.initials: DM
authors.lastname: Zaiss
authors.affiliation: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10021; dartis@med.cornell.edu.
authors.forename: David
authors.initials: D
authors.lastname: Artis
mesh_terms: D066258:Amphiregulin; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D066255:EGF Family of Proteins / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D004848:Epithelium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000502:physiology*; D025461:Feedback, Physiological; D007113:Immunity, Innate / Q000502:physiology*; D018928:Immunity, Mucosal / Q000502:physiology*; D016219:Immunotherapy, Adoptive; D000067596:Interleukin-33 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000145:classification / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins / Q000096:biosynthesis; D010581:Peyer's Patches / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D009077:Mucins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016264:Dextran Sulfate; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: inflammatory bowel disease; innate immunity; innate lymphoid cell; interleukin-33