Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) β, and under diabetic conditions, this IFNβ-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.

中文翻译：

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组蛋白甲基转移酶Setdb2调节糖尿病伤口修复中的巨噬细胞表型和尿酸生成。

巨噬细胞可塑性对于正常组织修复至关重要，以确保从炎症阶段恢复到增殖阶段。我们检查了从患有糖尿病的患者和健康对照组的伤口中分离出的巨噬细胞，发现甲基转移酶Setdb2的差异表达。Setdb2的髓样特异性缺失损害了正常伤口愈合中巨噬细胞从炎性表型向修复性表型的过渡。从机理上讲，Setdb2在炎性细胞因子基因启动子上的NF-κB结合位点使组蛋白3三甲基化，以抑制转录。伤口巨噬细胞中Setdb2的表达受干扰素（IFN）β调节，在糖尿病条件下，该IFNβ-Setdb2轴受损，导致糖尿病伤口中持续存在炎性巨噬细胞表型。Setdb2调节了黄嘌呤氧化酶的表达，从而调节了巨噬细胞中嘌呤分解代谢的尿酸（UA）途径，Setdb2或UA途径的药理靶向作用改善了愈合。因此，Setdb2在正常和病理性伤口修复过程中调节巨噬细胞可塑性，并且是治疗性操作的目标。