Inflammatory macrophages prevent colonic goblet and enteroendocrine cell differentiation through Notch signaling

Inflammatory macrophages in the intestine are a key pathogenic factor driving inflammatory bowel disease (IBD). Here, we report the role of inflammatory macrophage-mediated notch signaling on secretory lineage differentiation in the intestinal epithelium. Utilizing IL-10-deficient (Il10^-/-) mice, a model of spontaneous colitis, we found an increase in Notch activity in the colonic epithelium as well as an increase in intestinal macrophages expressing Notch ligands, which are increased in macrophages upon inflammatory stimuli. Furthermore, a co-culture system of inflammatory macrophages and intestinal stem and proliferative cells during differentiation reduced goblet and enteroendocrine cells. This was recapitulated when utilizing a Notch agonist on human colonic organoids (colonoids). In summary, our findings indicate that inflammatory macrophages upregulate notch ligands that activate notch signaling in ISC via cell-cell interactions, which in turn inhibits secretory lineage differentiation in the gastrointestinal (GI) tract.