PMID- 26243875 OWN - NLM STAT- MEDLINE DCOM- 20151230 LR - 20220129 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 112 IP - 34 DP - 2015 Aug 25 TI - IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. PG - 10762-7 LID - 10.1073/pnas.1509070112 [doi] AB - 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. FAU - Monticelli, Laurel A AU - Monticelli LA AD - 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; FAU - Osborne, Lisa C AU - Osborne LC AD - 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; FAU - Noti, Mario AU - Noti M AD - Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland; FAU - Tran, Sara V AU - Tran SV AD - 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; FAU - Zaiss, Dietmar M W AU - Zaiss DM AD - Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, Scotland, United Kingdom. FAU - Artis, David AU - Artis D AD - 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. LA - eng GR - R01 AI074878/AI/NIAID NIH HHS/United States GR - AI061570/AI/NIAID NIH HHS/United States GR - P01 AI106697/AI/NIAID NIH HHS/United States GR - T32 AI007532/AI/NIAID NIH HHS/United States GR - AI102942/AI/NIAID NIH HHS/United States GR - AI106697/AI/NIAID NIH HHS/United States GR - AI074878/AI/NIAID NIH HHS/United States GR - AI087990/AI/NIAID NIH HHS/United States GR - 095831/WT_/Wellcome Trust/United Kingdom GR - R01 AI102942/AI/NIAID NIH HHS/United States GR - AI095608/AI/NIAID NIH HHS/United States GR - U01 AI095608/AI/NIAID NIH HHS/United States GR - R01 AI061570/AI/NIAID NIH HHS/United States GR - AI097333/AI/NIAID NIH HHS/United States GR - MR/M011755/1/MRC_/Medical Research Council/United Kingdom GR - R01 AI095466/AI/NIAID NIH HHS/United States GR - T32AI007532/AI/NIAID NIH HHS/United States GR - R21 AI087990/AI/NIAID NIH HHS/United States GR - R01 AI097333/AI/NIAID NIH HHS/United States GR - AI095466/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150804 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Amphiregulin) RN - 0 (Areg protein, mouse) RN - 0 (EGF Family of Proteins) RN - 0 (Il33 protein, mouse) RN - 0 (Interleukin-33) RN - 0 (Mucins) RN - 0 (RNA, Messenger) RN - 0 (Recombinant Proteins) RN - 9042-14-2 (Dextran Sulfate) RN - EC 2.7.10.1 (EGFR protein, mouse) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Amphiregulin MH - Animals MH - Colitis/chemically induced/*immunology/therapy MH - Dextran Sulfate/toxicity MH - Disease Models, Animal MH - EGF Family of Proteins/deficiency/*physiology/therapeutic use MH - Epithelium/immunology/metabolism/pathology MH - ErbB Receptors/*physiology MH - Feedback, Physiological MH - Immunity, Innate/*physiology MH - Immunity, Mucosal/*physiology MH - Immunotherapy, Adoptive MH - Interleukin-33/biosynthesis/genetics/*physiology/therapeutic use MH - Intestinal Mucosa/immunology/pathology MH - Lung/immunology/pathology MH - Lymphocytes/classification/*immunology MH - Mice MH - Mice, Knockout MH - Mucins/biosynthesis MH - Peyer's Patches/immunology/pathology MH - RNA, Messenger/biosynthesis/genetics MH - Recombinant Proteins/therapeutic use MH - Signal Transduction MH - Specific Pathogen-Free Organisms PMC - PMC4553775 OTO - NOTNLM OT - inflammatory bowel disease OT - innate immunity OT - innate lymphoid cell OT - interleukin-33 COIS- The authors declare no conflict of interest. EDAT- 2015/08/06 06:00 MHDA- 2015/12/31 06:00 PMCR- 2016/02/25 CRDT- 2015/08/06 06:00 PHST- 2015/08/06 06:00 [entrez] PHST- 2015/08/06 06:00 [pubmed] PHST- 2015/12/31 06:00 [medline] PHST- 2016/02/25 00:00 [pmc-release] AID - 1509070112 [pii] AID - 201509070 [pii] AID - 10.1073/pnas.1509070112 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):10762-7. doi: 10.1073/pnas.1509070112. Epub 2015 Aug 4.