Skin ulcers resulting from impaired wound healing are a serious complication of diabetes. Unresolved inflammation, associated with the dysregulation of both the phenotype and function of macrophages, is involved in the poor healing of diabetic wounds. Here, we report that topical pharmacological inhibition of the mineralocorticoid receptor (MR) by canrenoate or MR small interfering RNA can resolve inflammation to improve delayed skin wound healing in diabetic mouse models; importantly, wounds from normal mice are unaffected. The beneficial effect of canrenoate is associated with an increased ratio of anti-inflammatory M2 macrophages to proinflammatory M1 macrophages in diabetic wounds. Furthermore, we show that MR blockade leads to downregulation of the MR target, LCN2, which may facilitate macrophage polarization toward the M2 phenotype and improve impaired angiogenesis in diabetic wounds. Indeed, diabetic LCN2-deficient mice showed improved wound healing associated with macrophage M2 polarization and angiogenesis. In addition, recombinant LCN2 protein prevented IL-4-induced macrophage switch from M1 to M2 phenotype. In conclusion, topical MR blockade accelerates skin wound healing in diabetic mice via LCN2 reduction, M2 macrophage polarization, prevention of inflammation, and induction of angiogenesis.

中文翻译：

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通过局部盐皮质激素受体阻滞剂改善糖尿病小鼠的皮肤伤口愈合。

伤口愈合不良导致的皮肤溃疡是糖尿病的严重并发症。与巨噬细胞的表型和功能失调相关的未解决的炎症与糖尿病伤口的不良愈合有关。在这里，我们报道了牛磺酸或MR小干扰RNA对盐皮质激素受体（MR）的局部药理抑制作用可以解决炎症，从而改善糖尿病小鼠模型中皮肤伤口的延迟愈合；重要的是，正常小鼠的伤口不受影响。Canrenoate的有益作用与糖尿病伤口中抗炎M2巨噬细胞与促炎M1巨噬细胞比例的增加有关。此外，我们显示MR封锁会导致MR目标LCN2的下调，这可能有助于巨噬细胞向M2表型极化，并改善糖尿病伤口的血管生成受损。确实，患有糖尿病的LCN2缺乏症小鼠表现出与巨噬细胞M2极化和血管生成相关的伤口愈合改善。此外，重组LCN2蛋白可阻止IL-4诱导的巨噬细胞从M1型转变为M2型。总之，局部MR阻滞通过LCN2减少，M2巨噬细胞极化，预防炎症和诱导血管生成来加速糖尿病小鼠皮肤伤口的愈合。