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

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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Fig. 1: ILC3s protect the intestinal epithelium from TNF-induced cell death.
Fig. 2: ILC3s are a major cellular source of HB-EGF in the intestine.
Fig. 3: ILC3-derived HB-EGF protects the intestinal epithelium from TNF.
Fig. 4: ILC3s produce PGE2 in response to IL-1β.
Fig. 5: PGE2 elicits ILC3-intrinsic HB-EGF production through the EP2 receptor.
Fig. 6: ILC3-derived HB-EGF protects from acute intestinal damage and inflammation.
Fig. 7: HB-EGF–producing ILC3s protect from chronic intestinal inflammation and are altered in IBD.

Data availability

scRNA-seq data are available at Gene Expression Omnibus under accession number GSE166266. All data sets generated and/or analyzed during the current study are presented in this published article, the accompanying source data or supplementary information or are available from the corresponding author upon reasonable request. Source data are provided with this paper.

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Acknowledgements

We thank members of the Sonnenberg Laboratory for discussions and critical reading of the manuscript, the Epigenomics Core of Weill Cornell Medicine and R.C. Harris for sharing critical mouse lines. Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274 and R01AI162936), the National Institute of Allergy and Infectious Diseases Mucosal Immunology Studies Team, the Searle Scholars Program, the American Asthma Foundation Scholar Award, an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative, Linda and Glenn Greenberg, the Dalton Family Foundation and the Roberts Institute for Research in IBD. L.Z. and W.Z. are supported by fellowships from the Crohn’s and Colitis Foundation (608975 and 831404, respectively). C.C. is supported by a Sackler Brain and Spine Institute research grant. A.M.J. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (T32DK116970). G.F.S. is supported by the Cancer Research Institute Lloyd J. Old STAR Program.

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Authors and Affiliations

Authors

Contributions

L.Z. and G.F.S. conceived the project. L.Z. performed most experiments and analyzed the data. W.Z., A.M.J., C.C., B.F., F.T., M.L. and H.Y. helped with experiments and data analyses. G.G.P. performed bioinformatics analyses. E.M., G.E. and K.I.A. provided essential mouse models, scientific advice and expertise. L.Z. and G.F.S. wrote the manuscript, with input from all authors.

Corresponding authors

Correspondence to Lei Zhou or Gregory F. Sonnenberg.

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The authors declare no competing interests.

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Nature Immunology thanks Arthur Kaser and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 The role of ILC3s and IL-22 in TNF-induced intestinal epithelial cell death.

a, Experimental design of the assay. b, Mice in (a) were examined for the depletion efficiency of ILC3s in the small intestine. (n = 3). c, CD90.2 levels in ILC2s or ILC3s were determined in IgG control mice. (n = 3 individual mice). d, Mice in (a) were examined for the depletion efficiency of ILC2s in the small intestine. (n = 3). e, Representative immunofluorescence sections and quantifications of TUNEL staining of the small intestine from noted mice 4 hours post recombinant TNF injection (N = 3 mice per group, n = 24 fields quantified per group). f, Mice in (a) were examined for the neutralization efficiency of endogenous IL-22 (n = 3 individual mice). Data are representative of two independent experiments, shown as the means ± S.E.M. Statistics are calculated by unpaired two-tailed Student’s t-test (b–d and f) or one-way ANOVA (e). Scale bars=50 μm.

Source data

Extended Data Fig. 2 Signature gene expression of ILC clusters in the scRNA-seq data set.

Small intestinal ILCs were sort-purified from PBS- or TNF-treated mice and determined by scRNA-Seq. UMAP shows the relative expression of signature genes in all clusters of each treatment condition.

Extended Data Fig. 3 ILC3s express HB-EGF in the large intestine.

a, Flow cytometry plots show HB-EGF expression in large intestine lamina propria (LI-LP) of noted mice as measured by conversion of the fluorescent LacZ substrate fluorescein di-β-d-galactopyranoside (FDG). b, Graph of frequency of HB-EGF+ cells in SI-LP of noted mice as measured by LacZ activity (n = 5 individual mice). c–e, Flow cytometry plots (c), graph of frequency (d) and quantification of cell number (e) of HB-EGF+ cells in LI-LP of noted mice as measured by LacZ activity (n = 4 individual mice). In both small and large intestines, CD4+ T cells were gated on CD45+CD3ε+CD4+, macrophages were gated on CD45+CD11b+CD11c+MHC II+CD64+, dendritic cells were gated on CD45+CD11b+CD11c+MHCII+CD64-, ILC2s were gated on CD45+Lin- CD127+CD90.2+KLRG1+, ILC3s were gated on CD45+Lin-CD127+CD90.2+KLRG1-CD45dim CCR6+. Lineage 1: CD3ε, CD5, CD8α, NK1.1, TCRγδ. Lineage 2: CD11b, CD11c, B220. Data in a-e are representative of two or three independent experiments, shown as the means ± S.E.M. Statistics are calculated by one-way ANOVA.

Source data

Extended Data Fig. 4 HB-EGF protects from TNF-induced intestinal epithelial cell death.

a–c, Cell death was induced in the murine rectum epithelial cell line CMT-93 by TNF and a cIAP inhibitor. Cell death was determined by representative flow cytometric analysis of cleaved-caspase 3 (a) or cleaved-caspase 8 (c) in the presence or absence of recombinant HB-EGF. Cell death was determined by representative flow cytometric analysis of cleaved-caspase 3 in the presence of various inhibitors (b). Data in a and b are representative of three independent experiments, data in c are pooled from three independent experiments, shown as the means ± S.E.M. Statistics are calculated by one-way ANOVA.

Source data

Extended Data Fig. 5 A PGE2-EP2 axis controls HB-EGF expression in ILC3s.

a, qPCR analysis of Hbegf expression in sort-purified ILC3s cultured with or without TNF treatment, relative to Hprt (n = 4 individual mice). b,c, UMAP show the expression of Ptgs2 (b) or Ptges (c) gene in all clusters of each treatment condition. The dotted line indicates CCR6+ ILC3 clusters. d. qPCR analysis of Hbegf expression in sort-purified ILC3s cultured with or without retinoic acid, relative to Hprt (n = 6). e, Bar graph of the frequencies of IL-17A, IL-22, IFN-γ or GM-CSF in ILC3s in the presence or absence of PGE2 stimulation ex vivo (n = 6). f, qPCR examination of Hbegf transcript in sort-purified ILC3s in the presence of various stimulus, relative to Hprt (n = 4 individual mice). g, Flow cytometry plots with graph of the frequencies of HB-EGF+ immune cells in small intestine of RorccreHbegff/- mice with or without EP2 agonist in vivo treatment (n = 3 individual mice of Mock and n = 4 individual mice of EP2 agonist). h, Western blot analysis of pro-HB-EGF in sort-purified ILC2s or ILC3s from small intestine of Rag1−/− mice with or without EP2 agonist in vivo treatment. i. Sex- and age- matched Ptger2f/f and RorccrePtger2f/f mice were examined for the deletion efficiency of EP2 in ILC3s in the small intestines by qPCR, relative to Hprt (n = 6 individual mice). j, Sort-purified ILC3s were stimulated with IL-1β in the presence or absence of EP2 antagonist, Hbegf expression was then examined by qPCR (n = 6 individual mice). Data in a and f–h are representative of two independent experiments, data in d, e, i and j are pooled from two independent experiments, shown as the means ± S.E.M. Statistics are calculated by unpaired (a, g and i) or paired (d and e) two-tailed Student’s t-test or one-way ANOVA (f and j). *, non-specific band.

Source data

Extended Data Fig. 6 ILC3-derived HB-EGF does not impact immune homeostasis in the healthy gut.

a,b, Flow cytometry plots with graph of frequencies and quantification of cell numbers of ILC3s (a) or IL-22+ ILC3s (b) in the large intestine of Hbegff/f and HbegfILC3 mice at steady state (n = 5 individual mice). c, Graph of frequencies and quantification of cell numbers of T cell subsets in the large intestine of Hbegff/f and HbegfILC3 mice at steady state (n = 5 individual mice). Data in a-c are representative of two independent experiments, shown as the means ± S.E.M. Statistics are calculated by unpaired two-tailed Student’s t-test.

Source data

Extended Data Fig. 7 Loss of T cell–derived HB-EGF does not alter susceptibility to experimental intestinal inflammation.

a–c, Hbegff/f and HbegfT cell mice were given 3% DSS for 6 days, disease and recovery were monitored by weight loss (a), colon shortening (b) and H&E staining of the distal colon (c) at day 11 (n = 5 individual mice). Data in ac are representative of two independent experiments, shown as the means ± S.E.M. Statistics are calculated by unpaired two-tailed Student’s t-test. Scale bars=100 μm.

Source data

Extended Data Fig. 8 Intestinal epithelial cell responses in the absence of ILC3-specific HB-EGF.

ad, Hbegff/f and HbegfILC3 mice were challenged with 3% DSS for 6 days (n = 6 individual mice). The functional ability of intestinal epithelium was analyzed, including anti-microbial peptides production (a), tight junction proteins expression (b), stem cell composition (c) and proliferative ability (d) (N = 4 individual mice per group, n = 27 crypts quantified per group). e, Schematic model of chronic colitis induction. Data in ad are representative of two independent experiments, shown as the means ± S.E.M. Statistics are calculated by unpaired two-tailed Student’s t-test. Scale bars=50 μm.

Source data

Extended Data Fig. 9 ILC3s produce HB-EGF to protect the intestine from TNF.

Here we define a novel pathway of tissue protection in the mammalian intestine. Briefly, ILC3s sense intestinal damage or inflammation through IL-1β release, which amplifies ILC3 responses through a PGE2-EP2 axis, subsequently promoting HB-EGF production and protection against TNF-induced cell death in the intestinal epithelium.

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Zhou, L., Zhou, W., Joseph, A.M. et al. Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation. Nat Immunol 23, 251–261 (2022). https://doi.org/10.1038/s41590-021-01110-0

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