Treadmill exercise alleviates STING-mediated microglia pyroptosis and polarization via activating mitophagy post-TBI

作者：Jie Chen, Tong Zhu, Xixi Yang, Zhuojin Yang, Mengqing Shen, Boyuan Gu, Danmei Wang, Yuxiang Zhang, Mingxia Zhang, Siyu Sun, Jun Yu, Chunxia Yan · 发表于：Free Radical Biology and Medicine · 年份：2025 · DOI：10.1016/j.freeradbiomed.2025.07.034 · 被引用次数：8 · 研究领域：Inflammasome and immune disorders、Autophagy in Disease and Therapy、interferon and immune responses

Moderate-intensity treadmill exercise has emerged as a promising therapeutic intervention for traumatic brain injury (TBI), yet its precise mechanisms remain unclear. Emerging evidence suggests that STING-mediated microglial pyroptosis and polarization might exacerbate TBI-induced pathological damage. Our previous work demonstrated treadmill exercise's inhibitory effects on the STING level, and mitophagy has been recognized as a crucial regulator of STING activity. Therefore, we aimed to test the possibility that treadmill exercise alleviates STING-mediated microglia pyroptosis and polarization partially through activating mitophagy post-TBI. First, we found that TBI-induced pyroptosis primarily occurred in neurons and microglia, along with pro-inflammatory M1 microglial polarization in the injured cortex. Remarkably, treadmill exercise could effectively reverse those pathological changes, demonstrating its anti-pyroptotic and anti-inflammatory potential. Then, we explored the dynamic expression of STING post-TBI, and found a progressively increased trend of STING in neurons, astrocytes, and microglia from 6 h to 35 days after TBI, with the most prominent rise in microglia. Notably, STING knockdown markedly diminished TBI-induced pyroptosis and prompted a shift in microglial polarization from M1 to M2. Furthermore, STING overexpression could partly abolish the treadmill exercise's neuroprotective effects against pyroptosis and inflammation post-TBI, suggesting that the anti-p...