Dimethyl fumarate modulates M1/M2 macrophage polarization to ameliorate periodontal destruction by increasing TUFM-mediated mitophagy

Abstract

Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues. Dimethyl fumarate (DMF) has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions. Here, we investigated for the first time the therapeutic effect of DMF on periodontitis. In vivo studies showed that DMF significantly inhibited periodontal destruction, enhanced mitophagy, and decreased the M1/M2 macrophage ratio. In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages, with improved mitochondrial function, inhibited oxidative stress, and increased mitophagy in RAW 264.7 cells. Furthermore, DMF increased intracellular mitochondrial Tu translation elongation factor (TUFM) levels to maintain mitochondrial homeostasis, promoted mitophagy, and modulated macrophage polarization, whereas TUFM knockdown decreased the protective effect of DMF. Finally, mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway. Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages, resulting in a shift in the balance of macrophage polarization, thereby attenuating periodontitis. Importantly, this study provides new insights into the prevention of periodontitis.

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Funding

Natural Science Foundation of China (grant nos. 82270991), Zhejiang Provincial Natural Science Foundation of China/Outstanding Youth Science Foundation (grant no. LR21H140002), Medical Health Science and Technology Major Project of Zhejiang Provincial Health Commission (grant no. WKJ-ZJ-2311), Wenzhou Science and Technology Bureau Public Welfare Social Development (Medical and Health) Science and Technology Project (grant no. ZY2021015), Opening Research Fund from Shanghai Key Laboratory of Stomatology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine (grant no. 2022SKLS-KFKT011), Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research (grant no. GXKLRROM2106)

State Key Laboratory of Oral Diseases Open Fund (grant no. SKLOD2024OF08)

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