IFN-γ-dependent epigenetic regulation instructs colitogenic monocyte/macrophage lineage differentiation in vivo

Colonic macrophages induce pathogenic inflammation against commensal bacteria, leading to inflammatory bowel disease (IBD). Although the ontogeny of colonic macrophages has been well studied in the past decade, how macrophages gain colitogenic properties during the development of colitis is unknown. Using a chemically induced colitis model, we showed that accumulated Ly6C⁺ cells consisting of inflammatory monocytes and inflammatory macrophages strongly expressed representative colitogenic mediators such as tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS). The interferon-γ-signal transducer and activator of transcription 1 (IFN-γ-Stat1) pathway was required for generating colitogenic macrophages, given that Stat1^-/- mice had less severe colitis and fewer colitogenic macrophages. Notably, IFN-γ induced histone acetylation at the promoter regions of the Tnf and Nos2 loci in the monocyte and macrophage lineage, indicating that IFN-γ-dependent epigenetic regulation instructs the development of the colitogenic monocyte and macrophage lineage in vivo. Collectively, our results provide the essential mechanism by which dysregulated colitogenic monocytes/macrophages develop at the colon mucosa during inflammation, and suggest a new drug target for treating IBD.