SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury

Abstract

Background Axonal degeneration is a common pathological feature in many acute and chronic neurological diseases such as spinal cord injury (SCI). SARM1 (sterile alpha and TIR motif containing 1), the fifth TLR (Toll-like receptor) adaptor, has diverse functions in the immune and nervous systems, and recently has been identified as a key mediator of Wallerian degeneration (WD). However, the detailed functions of SARM1 after SCI still remain unclear. Methods Modified Allen’s method was used to establish a contusion model of SCI in mice. Furthermore, to address the function of SARM1 after SCI, mice that SARM1 was conditionally knockout (CKO) in the central nervous system (CNS), namely SARM1Nestin-CKO mice, were successfully generated. And to explore the potential of clinical application, FK866, an inhibitor of SARM1, was used to further verify the phenomenon and mechanism. Results We found that SARM1 was mainly detected in neurons and was upregulated in neurons at early stage after SCI. And SARM1Nestin-CKO mice displayed normal development of the spinal cords and motor function. Interestingly, conditional deletion of SARM1 in neurons promoted the recovery of behavior performance after SCI. Mechanistically, conditional deletion of SARM1 in neurons promoted neuronal regeneration at intermediate phase after SCI, and reduced neuroinflammation at SCI early phase, which may through downregulation of NF-κB signaling after SCI. Finally, FK866 reduced neuroinflammation and promoted neuronal regeneration after SCI. Conclusion Our results indicate that SARM1-mediated prodegenerative pathway and neuroinflammation promotes the pathological progress of SCI and anti-SARM1 therapeutics are a viable and promising approach for preserving neuronal function after SCI.