Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation

Nat Immunol. 2022 Feb;23(2):251-261. doi: 10.1038/s41590-021-01110-0.

Lei Zhou ¹ ² ³, Wenqing Zhou ⁴ ⁵ ⁶, Ann M Joseph ⁴ ⁵ ⁶, Coco Chu ⁶, Gregory G Putzel ⁶, Beibei Fang ⁷, Fei Teng ⁴ ⁵ ⁶, Mengze Lyu ⁴ ⁵ ⁶, Hiroshi Yano ⁶, Katrin I Andreasson ⁸, Eisuke Mekada ⁹, Gerard Eberl ¹⁰, Gregory F Sonnenberg ¹¹ ¹² ¹³

Affiliations

1 Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, New York, NY, USA. lez2004@med.cornell.edu.
2 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA. lez2004@med.cornell.edu.
3 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA. lez2004@med.cornell.edu.
4 Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, New York, NY, USA.
5 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA.
6 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA.
7 Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
8 Department of Neurology & Neurological Sciences, Stanford Neuroscience Institute, Stanford Immunology Program, Stanford School of Medicine, Stanford, CA, USA.
9 Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
10 Microenvironment and Immunity Unit, Institut Pasteur, Paris, France.
11 Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, New York, NY, USA. gfsonnenberg@med.cornell.edu.
12 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA. gfsonnenberg@med.cornell.edu.
13 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA. gfsonnenberg@med.cornell.edu.

PMID: 35102343 DOI: 10.1038/s41590-021-01110-0

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.

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