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PAQR3 depletion accelerates diabetic wound healing by promoting angiogenesis through inhibiting STUB1-mediated PPARγ degradation

Abstract

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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Fig. 1: PAQR3 silencing promotes wound healing and angiogenesis in diabetic mice.
Fig. 2: PAQR3 silencing activates M2 macrophage polarization and elevates PPARα/γ expression in wounded skin tissues of diabetic mice.
Fig. 3: PAQR3 silencing promotes M2 macrophage polarization and enhances PPARγ expression in PMA-treated THP-1 cells.
Fig. 4: PAQR3 silencing promotes the migration of keratinocytes and enhances the angiogenic ability of HUVECs.
Fig. 5: PAQR3 mediates PPARγ protein degradation via the ubiquitination pathway.
Fig. 6: PAQR3 interacts with the E3 ubiquitin ligase STUB1 to promote PPARγ protein degradation in macrophages.
Fig. 7: PAQR3 silencing-induced M2 macrophage polarization is dependent on STUB1-mediated PPARγ ubiquitination.

Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Contributions

J.Q. conceived and designed the work that led to the submission. X.L. acquired data. W.-C.Z. played an important role in interpreting the results. J.Q. drafted, and C.S. revised the manuscript. All authors approved the final version.

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Correspondence to Chang Shu.

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The authors declare no competing interests.

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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

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  • DOI: https://doi.org/10.1038/s41374-022-00786-8

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