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.
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The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
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The authors declare no competing interests.
Ethics approval and consent to participate
All experimental operations on mice were approved in advance by the Experimental Animal Ethics Committee of the Second Xiangya Hospital, Central South University, and performed strictly according to the Guide for the Care and Use of Laboratory Animals designated by the National Research Council.
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Qiu, J., Shu, C., Li, X. et al. PAQR3 depletion accelerates diabetic wound healing by promoting angiogenesis through inhibiting STUB1-mediated PPARγ degradation. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00786-8