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.

中文翻译：

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IFN-γ 依赖性表观遗传调控在体内指导大肠杆菌单核细胞/巨噬细胞谱系分化。

结肠巨噬细胞诱导针对共生细菌的致病性炎症，导致炎症性肠病 (IBD)。尽管结肠巨噬细胞的个体发育在过去十年中得到了很好的研究，但巨噬细胞在结肠炎发展过程中如何获得致结肠炎特性尚不清楚。使用化学诱导的结肠炎模型，我们发现由炎性单核细胞和炎性巨噬细胞组成的累积的 Ly6C ⁺细胞强烈表达代表性的致结肠炎介质，如肿瘤坏死因子-α (TNF-α) 和诱导型一氧化氮合酶 (iNOS)。鉴于 Stat1 ^-/-小鼠的结肠炎较轻，致结肠炎的巨噬细胞较少。值得注意的是，IFN-γ 在单核细胞和巨噬细胞谱系中 Tnf 和 Nos2 基因座的启动子区域诱导组蛋白乙酰化，表明 IFN-γ 依赖性表观遗传调控指导体内致大肠杆菌单核细胞和巨噬细胞谱系的发育。总的来说，我们的研究结果提供了炎症期间结肠粘膜失调的致结肠炎单核细胞/巨噬细胞发育的基本机制，并提出了治疗 IBD 的新药物靶点。