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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 34; pp. 10762 - 10767
• Main Authors: Monticelli, Laurel A., Osborne, Lisa C., Noti, Mario, Tran, Sara V., Zaiss, Dietmar M. W., Artis, David
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.08.2015; National Acad Sciences
• Subjects: Amphiregulin; Animals; Biological Sciences; Cells; Colitis - chemically induced; Colitis - immunology; Colitis - therapy; Cytokines; Dextran Sulfate - toxicity; Disease Models, Animal; EGF Family of Proteins - deficiency; EGF Family of Proteins - physiology; EGF Family of Proteins - therapeutic use; Epidermal growth factor; Epithelium - immunology; Epithelium - metabolism; Epithelium - pathology; ErbB Receptors - physiology; Feedback, Physiological; Homeostasis; Immunity, Innate - physiology; Immunity, Mucosal - physiology; Immunotherapy, Adoptive; Interleukin-33 - biosynthesis; Interleukin-33 - genetics; Interleukin-33 - physiology; Interleukin-33 - therapeutic use; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Lung - immunology; Lung - pathology; Lymphocytes - classification; Lymphocytes - immunology; Mice; Mice, Knockout; Mucins - biosynthesis; Peyer's Patches - immunology; Peyer's Patches - pathology; Recombinant Proteins - therapeutic use; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Rodents; Signal Transduction; Specific Pathogen-Free Organisms; Tissues; innate lymphoid cell; innate immunity; interleukin-33; inflammatory bowel disease
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1509070112

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.