SENP3 deletion promotes M2 macrophage polarization and accelerates wound healing through smad6/IκB/p65 signaling pathway

Yiwen Ma; Jiateng Hu; Xingjuan Xue; Jianmin Gu; Yuyan Pan; Jun Yang

doi:10.1016/j.heliyon.2023.e15584

SENP3 deletion promotes M2 macrophage polarization and accelerates wound healing through smad6/IκB/p65 signaling pathway

Heliyon. 2023 Apr 25;9(5):e15584. doi: 10.1016/j.heliyon.2023.e15584. eCollection 2023 May.

Authors

Yiwen Ma¹, Jiateng Hu^{2

3}, Xingjuan Xue⁴, Jianmin Gu⁵, Yuyan Pan⁶, Jun Yang¹

Affiliations

¹ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
² Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
³ Vascular Centre of Shanghai Jiao Tong University, Shanghai, 200011, China.
⁴ Department of Thoracic Surgery, Fuqing City Hospital Affiliated to Fujian Medical University, Fuqing City, Fujian Province, 350399, China.
⁵ Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
⁶ Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Abstract

Macrophages preferentially polarize to the anti-inflammatory M2 subtype in response to alterations in the wound microenvironment. SUMO-specific protease 3 (SENP3), a SUMO-specific protease, has been proven to regulate inflammation in macrophages by deSUMOylating substrate proteins, but its contribution to wound healing is poorly defined. Here, we report that SENP3 deletion promotes M2 macrophage polarization and accelerates wound healing in macrophage-specific SENP3 knockout mice. Notably, it affects wound healing through the suppression of inflammation and promotion of angiogenesis and collagen remodeling. Mechanistically, we identified that SENP3 knockout facilitates M2 polarization through the Smad6/IκB/p65 signaling pathway. SENP3 knockout elevated the expression of Smad6 and IκB. Moreover, Smad6 silencing enhanced the expression of p-p65 and proinflammatory cytokines while inhibiting the level of IκB. Our study revealed the essential role of SENP3 in M2 polarization and wound healing, which offers a theoretical basis for further research and a therapeutic strategy for wound healing.

Keywords: Inflammatory response; Macrophage polarization; SENP3; Smad6/IκB/p65 signaling pathway; Wound healing.