期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 34, 页码 10762-10767出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1509070112
关键词
innate immunity; innate lymphoid cell; interleukin-33; inflammatory bowel disease
资金
- National Institutes of Health [AI061570, AI095608, AI087990, AI074878, AI095466, AI106697, AI102942, AI097333, T32AI007532]
- Crohns and Colitis Foundation of America
- Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award
- Edmond J. Safra Foundation/Cancer Research Institute Irvington Fellowship
- Swiss National Foundation Advanced Research Fellowships
- MRC [MR/M011755/1] Funding Source: UKRI
- Medical Research Council [MR/M011755/1] Funding Source: researchfish
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.
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