IL-10 inhibits STAT1-dependent macrophage accumulation during microbiota-induced colitis

Loss of IL-10R function leads to severe early onset colitis and in murine models is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed Stat1-/- mice exhibit defects in colonic macrophage accumulation following Helicobacter hepaticus infection and IL-10R blockade, and this was phenocopied in mice lacking IFNGR, an inducer of STAT1 activation. Radiation chimeras demonstrated that reduced accumulation of STAT1-deficient macrophages was based on a cell-intrinsic defect. Unexpectedly, mixed radiation chimeras generated with both WT and IL-10R-deficient bone marrow indicated that rather than directly interfering with STAT1 function, IL-10R prevents the generation of a cell extrinsic signal that promotes the accumulation of immature macrophages. These results define essential mechanisms controlling inflammatory macrophage accumulation in inflammatory bowel diseases. Summary Intrinsic STAT1-function drives the accumulation of macrophages within the colon following the loss of IL-10R signaling. IL-10R prevents this STAT1-dependent process through a non-cell autonomous mechanism. ### Competing Interest Statement Scott B. Snapper declares the following interests: scientific advisory board participation for Pfizer, BMS, Hoffman La Roche, Lilly, IFM Therapeutics, Merck, and Pandion; grant support from Pfizer, Novartis, Takeda, Amgen; consulting for Hoffman La Roche, Merck, Takeda, and Amgen. The authors have no additional financial interests. * HAI : histologic activity index Hh : Helicobacter hepaticus LP : lamina propria MΦ : macrophages