Group-3 innate lymphoid cells protect from intestinal inflammation via syndecan-4

Abstract

Abstract Group-3 innate lymphoid cells (ILC3s) are a recently described set of tissue resident immune cells which are enriched in the intestine, express RORγt, and secrete a variety of effector cytokines to orchestrate homeostasis, inflammation, and immunity. Crucially, intestinal ILC3 function and frequency is dysregulated during inflammatory bowel disease (IBD). However, it remains unclear how ILC3s sense and respond to the heterogeneity of signals present in the intestinal microenvironment or how this cell type becomes disrupted during intestinal inflammation. Recently, a single-cell RNA-sequencing analysis in our laboratory identified that syndecan-4 is highly expressed within ILC3s. Syndecans are a class of heparan sulfate proteoglycans which can become dysregulated in the intestinal epithelium and the lamina propria of IBD patients. Further, mice lacking global expression of syndecan-4 show a heightened susceptibility to models of intestinal inflammation. However, cell-specific and molecular mechanisms for this protection have yet to be elucidated. Here, we unexpectedly identify that syndecan-4 is significantly enriched among ILC3s relative to other intestinal immune cells. IL-1 selectively upregulates ILC3-specific syndecan-4, but during acute and chronic mouse modeling of intestinal inflammation, ILC3 expression of syndecan-4 is reduced. Mice lacking ILC3-specific syndecan-4 exhibit exacerbated susceptibility to intestinal inflammation resulting in greater loss of intestinal epithelial architecture compared to controls. Collectively, our data indicate that syndecan-4 represents a novel pathway by which ILC3s orchestrate intestinal health and limit tissue damage during inflammation. Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, R01AI162936 and R01CA274534), the NIAID Mucosal Immunology Studies Team (MIST), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, Linda and Glenn Greenberg, the Dalton Family Foundation, and the Roberts Institute for Research in IBD. B.F. is supported by the NIAID of the National Institutes of Health training grant T32 (5 T32 AI 134632-5). G.F.S. is a CRI Lloyd J. Old STAR.