Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, P.R. China.
Lab Invest. 2022 Oct;102(10):1121-1131. doi: 10.1038/s41374-022-00786-8. Epub 2022 Jun 16.
The pathogenesis of diabetic wounds is closely associated with the dysregulation of macrophage polarization. However, the underlying mechanism remains poorly understood. In this study, we aimed to investigate the potential effects of PAQR3 (progestin and adipoQ receptor 3) silencing in accelerating diabetic wound healing. We showed that PAQR3 silencing promoted skin wound healing and angiogenesis in diabetic mice, which was accompanied by enhanced M2 macrophage polarization and elevated expression of PPARγ (peroxisome proliferator-activated receptor γ). PAQR3 silencing also promoted M2 polarization and increased PPARγ protein level in PMA-treated THP-1 cells. Moreover, knockdown of PAQR3 in macrophages enhanced the migration of HaCaT cells and tube formation of HUVECs. The ubiquitination of PPARγ protein in macrophages was repressed by PAQR3 silencing. STUB1 (STIP1 homology and U-box-containing protein 1) binds with the PPARγ protein to mediate PPARγ ubiquitination and degradation in macrophages, which was impaired by PAQR3 silencing. The PPARγ inhibitor, GW9662, or STUB1 overexpression abrogated the enhanced M2 macrophage polarization induced by PAQR3 silencing. Therefore, these findings demonstrates that PAQR3 silencing accelerates diabetic wound healing by promoting M2 macrophage polarization and angiogenesis, which is mediated by the inhibition of STUB1-mediated PPARγ protein ubiquitination and degradation.
糖尿病伤口的发病机制与巨噬细胞极化失调密切相关。然而，其潜在机制仍不清楚。在本研究中，我们旨在研究沉默 PAQR3（孕激素和脂联素受体 3）在加速糖尿病伤口愈合中的潜在作用。结果表明，沉默 PAQR3 可促进糖尿病小鼠的皮肤伤口愈合和血管生成，这伴随着 M2 巨噬细胞极化的增强和 PPARγ（过氧化物酶体增殖物激活受体 γ）的表达升高。沉默 PAQR3 还可促进 PMA 处理的 THP-1 细胞中 M2 极化和增加 PPARγ 蛋白水平。此外，巨噬细胞中 PAQR3 的敲低增强了 HaCaT 细胞的迁移和 HUVECs 的管形成。巨噬细胞中 PPARγ 蛋白的泛素化受 PAQR3 沉默的抑制。STUB1（STIP1 同源和 U -box 包含蛋白 1）与 PPARγ 蛋白结合，介导巨噬细胞中 PPARγ 的泛素化和降解，沉默 PAQR3 会破坏这一过程。PPARγ 抑制剂 GW9662 或 STUB1 的过表达可阻断 PAQR3 沉默诱导的 M2 巨噬细胞极化增强。因此，这些发现表明，沉默 PAQR3 通过抑制 STUB1 介导的 PPARγ 蛋白泛素化和降解来促进 M2 巨噬细胞极化和血管生成，从而加速糖尿病伤口愈合。
