M5C-methylated EDIL3 attenuates spinal cord ischemia-reperfusion injury by suppressing neutrophil extracellular trap formation.

Abstract

The formation of neutrophil extracellular traps (NETs) at the injury site contributes to secondary damage in spinal cord injury (SCI). This study investigated the function of EDIL3 in spinal cord ischemia-reperfusion injury (SCIRI) and its connection to NET formation. We established a mouse SCIRI model, which revealed significant neutrophil infiltration and NET formation within the injured spinal cord at 48 h post-reperfusion. Therapeutic disruption of NETs with DNase1 or EDIL3 overexpression ameliorated multiple aspects of SCIRI pathology, including tissue damage, blood-spinal cord barrier (BSCB) disruption, neuroinflammation, neuronal death, and motor deficits. Endothelial cell-specific knockout of EDIL3, however, intensified these injuries. Mechanistically, EDIL3 inhibited PMA-induced NET formation in vitro by attenuating NF-κB activation and protected the endothelial barrier from NET-mediated damage in co-culture assays. Moreover, NSUN2 promoted m5C methylation of EDIL3 mRNA, facilitating its YBX1-dependent stabilization. Crucially, the exacerbation of SCIRI following NSUN2 knockdown was abrogated by EDIL3 upregulation. Collectively, the NSUN2-EDIL3 axis represents a key endogenous pathway that limits BSCB disruption and neuronal death in SCIRI by restraining NET formation.