Fibroblast-ILC3 crosstalk restrains inflammation in the gut

Fibroblasts exhibit remarkable phenotypic and functional heterogeneity in chronic inflammatory diseases, but how these changes impact immune outcomes remain at early stages of investigation. Here we identify a unique fibroblast population that robustly expresses insulin-like growth factor 1 (IGF1) in the healthy intestine that are reduced in inflammatory bowel disease (IBD) patients and necessary to protect from experimental models of gut inflammation. In silico analyses reveal unexpected cross-talk between IGF1+ fibroblasts and group 3 innate lymphoid cells (ILC3s), which dominantly express the IGF-1 receptor (IGF1R) in the gut to protect from inflammation. Mechanistically, IGF1 limits ILC3 production of CXCL10 in inflammatory contexts to prevent recruitment of plasmacytoid dendritic cells (pDC) and restrain gut inflammation. Finally, IGF1 signaling reduces CXCL10 production in human ILC3s, but this pathway is altered in the inflamed intestine of IBD patients and inversely correlates with a higher frequency of pDC. Our results define an unexpected mechanism by which anti-inflammatory fibroblasts safeguard the gut by IGF1-dependent crosstalk with an innate lymphocyte-pDC axis.