Zhao Tianlun, Di Jiawei, Kang Yu, Zhang Haojie, Yao Senyu, Liu Bin, Rong Limin
Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, China.
Cell Prolif. 2025 May 4:e70047. doi: 10.1111/cpr.70047.
Microglia, considered as the main immune responder, play an important role in regulating neuroinflammation in central nervous system (CNS) disorders. Our previous work found that TREM2 is highly expressed in microglia and is related to their functional state. However, the specific role of TREM2 in spinal cord injury has not yet been explored. To further investigate the potential mechanism of TREM2, we performed single-cell sequencing on wild-type (Wt) and Trem2 mice before and after spinal cord injury. Compared to Wt mice, the lysosome, autophagy and membrane-related pathways are more strongly activated in Trem2 mice, suggesting that TREM2 may exert its effects by influencing lysosomal membranes and autophagy. Mechanistically, we demonstrated that the knockout of Trem2 can reduce the nuclear translocation of TFEB by decreasing the phosphorylation of Syk. Furthermore, we validated that in vitro and in vivo silencing Trem2 can promote autophagy by repairing lysosomal membrane permeabilization. Through immunofluorescence, 3D gait analysis, motor evoked potential experiments, H&E staining and Masson staining, we demonstrated that the increased level of autophagy can rescue more microglia in vivo and promote both functional and histological recovery of spinal cord injury. Collectively, these results not only suggest that microglial lysosomal autophagy is regulated in a TREM2-dependent LMP manner, but also, more importantly, they provide a promising clinical translation strategy based on gene therapy for lysosome-related central nervous system disorders.
小胶质细胞被认为是主要的免疫应答细胞，在调节中枢神经系统（CNS）疾病中的神经炎症方面发挥着重要作用。我们之前的研究发现，TREM2在小胶质细胞中高表达，且与它们的功能状态有关。然而，TREM2在脊髓损伤中的具体作用尚未得到探索。为了进一步研究TREM2的潜在机制，我们对脊髓损伤前后的野生型（Wt）小鼠和Trem2基因敲除小鼠进行了单细胞测序。与Wt小鼠相比，Trem2基因敲除小鼠的溶酶体、自噬和膜相关途径的激活更为强烈，这表明TREM2可能通过影响溶酶体膜和自噬来发挥其作用。从机制上讲，我们证明敲除Trem2可通过降低Syk的磷酸化来减少TFEB的核转位。此外，我们验证了在体外和体内沉默Trem2可通过修复溶酶体膜通透性来促进自噬。通过免疫荧光、三维步态分析、运动诱发电位实验、苏木精-伊红染色和Masson染色，我们证明自噬水平的提高可以在体内挽救更多的小胶质细胞，并促进脊髓损伤的功能和组织学恢复。总的来说，这些结果不仅表明小胶质细胞溶酶体自噬是以TREM2依赖的溶酶体膜通透性方式调节的，更重要的是，它们为基于基因治疗的溶酶体相关中枢神经系统疾病提供了一种有前景的临床转化策略。
