Lin Jiezhao, Sun Yuanfang, Huang Haoran, Yu Cheng, Kuang Wenhao, Wang Yihan, Zhu Lixin
Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
Department of Spinal Surgery, Shantou Central Hospital, Shantou, 515031, China.
Mol Neurobiol. 2025 Jun;62(6):7054-7074. doi: 10.1007/s12035-024-04631-5. Epub 2024 Nov 28.
Secondary injury presents a significant hurdle to neural regeneration following spinal cord injury (SCI), primarily driven by inflammation in which microglial cells play a crucial role. Despite the growing interest in mitophagy, studies on its occurrence post-spinal cord injury, particularly within microglial cells, are scarce. While P2Y6R has been implicated in inflammation regulation in various neurological conditions, its specific role in SCI remains uncertain. Our study revealed an upregulation of P2Y6R expression following SCI notably in microglial cells. Treatment with the P2Y6R-specific inhibitor, MRS2578, in mice facilitated M2 polarization of microglial cells and alleviated secondary damage, ultimately enhancing neural regeneration and functional recovery. In an in vitro BV2 inflammation model, our findings indicate that P2Y6R inhibition induced M2 polarization of BV2 cells and reduced neuroinflammation through PINK/Parkin-dependent mitophagy activation. In summary, our results underscore the potential of P2Y6R inhibition in promoting mitophagy-induced M2 polarization of microglial cells, thereby ameliorating secondary injury following spinal cord injury.
继发性损伤是脊髓损伤（SCI）后神经再生的重大障碍，主要由炎症驱动，其中小胶质细胞起着关键作用。尽管对线粒体自噬的兴趣日益增加，但关于脊髓损伤后尤其是小胶质细胞中线粒体自噬发生情况的研究却很少。虽然P2Y6R已被证明在各种神经疾病的炎症调节中起作用，但其在脊髓损伤中的具体作用仍不确定。我们的研究表明，脊髓损伤后P2Y6R表达上调，特别是在小胶质细胞中。在小鼠中用P2Y6R特异性抑制剂MRS2578治疗促进了小胶质细胞的M2极化，减轻了继发性损伤，最终增强了神经再生和功能恢复。在体外BV2炎症模型中，我们的研究结果表明，P2Y6R抑制通过PINK/Parkin依赖性线粒体自噬激活诱导BV2细胞的M2极化并减少神经炎症。总之，我们的结果强调了抑制P2Y6R在促进线粒体自噬诱导的小胶质细胞M2极化方面的潜力，从而改善脊髓损伤后的继发性损伤。
