TREM2 Impedes Recovery After Spinal Cord Injury by Regulating Microglial Lysosomal Membrane Permeabilization‐Mediated Autophagy

ABSTRACT 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.