Title | Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Zhou L, Zhou W, Joseph AM, Chu C, Putzel GG, Fang B, Teng F, Lyu M, Yano H, Andreasson KI, Mekada E, Eberl G, Sonnenberg GF |
Journal | Nat Immunol |
Volume | 23 |
Issue | 2 |
Pagination | 251-261 |
Date Published | 2022 02 |
ISSN | 1529-2916 |
Keywords | Animals, Epithelial Cells, Heparin-binding EGF-like Growth Factor, Immunity, Innate, Inflammation, Intestinal Mucosa, Intestines, Lymphocytes, Mice, Mice, Inbred C57BL, Signal Transduction, Tumor Necrosis Factor-alpha |
Abstract | Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor-like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD. |
DOI | 10.1038/s41590-021-01110-0 |
Alternate Journal | Nat Immunol |
PubMed ID | 35102343 |
PubMed Central ID | PMC8842850 |
Grant List | T32 DK116970 / DK / NIDDK NIH HHS / United States R01 AI162936 / AI / NIAID NIH HHS / United States R21 CA249274 / CA / NCI NIH HHS / United States R01 AI145989 / AI / NIAID NIH HHS / United States R01 AI123368 / AI / NIAID NIH HHS / United States R01 AI143842 / AI / NIAID NIH HHS / United States U01 AI095608 / AI / NIAID NIH HHS / United States |