The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair
The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair
复制标题
DOI：
10.1016/j.immuni.2019.06.015
复制
发表时间：
2019-08-20
期刊：
影响因子：
32.4
通讯作者：
Gallagher, Katherine A.
中科院分区：
文献类型：
--
作者：
Kimball, Andrew S.;Davis, Frank M.;Gallagher, Katherine A.
巨噬细胞的可塑性对于正常组织修复至关重要，以确保愈合从炎症阶段过渡到增殖阶段。我们检测了从糖尿病患者和健康对照者伤口分离的巨噬细胞，发现甲基转移酶Setdb2的表达差异。Setdb2的骨髓特异性缺失会破坏巨噬细胞在正常伤口愈合过程中从炎症表型向修复表型的转变。在机制上，Setdb2三甲基化炎症细胞因子基因启动子上NF-kappa B结合位点的组蛋白3以抑制转录。Setdb2在伤口巨噬细胞中的表达受干扰素(IFN) β调节，在糖尿病条件下，IFN β -Setdb2轴受损，导致糖尿病伤口中持续的炎症性巨噬细胞表型。Setdb2调节黄嘌呤氧化酶的表达，从而调节巨噬细胞嘌呤分解代谢的尿酸（UA）途径，药理靶向Setdb2或UA途径可改善愈合。因此，Setdb2在正常和病理性伤口修复过程中调节巨噬细胞的可塑性，是治疗操作的靶点。
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-kappa B binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) beta, and under diabetic conditions, this IFN beta-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.