Deletion of SIRPα (signal regulatory protein-α) promotes phagocytic clearance of myelin debris in Wallerian degeneration, axon regeneration, and recovery from nerve injury

Abstract

Abstract Background Recovery of function from traumatic nerve injury depends on the ability of severed axons to grow/regenerate back to their target tissues. This is achieved by successfully crossing the lesion site where physical impact severed axons, determined by the type of trauma, followed by successfully growing throughout the Wallerian degenerating nerve segment located distal to and beyond the lesion site, determined by the nature of Wallerian degeneration. The protracted removal of myelin debris in Wallerian degeneration, which leads residual myelin debris to slow down axon growth, impedes recovery of function. We focused in this study on mechanism(s) that delay the removal of myelin debris in Wallerian degeneration and so impede recovery. Previously, we showed that myelin debris inhibited its own phagocytosis in primary cultured macrophages and microglia as CD47 on myelin ligated SIRPα (signal regulatory protein-α) on phagocytes, and sequentially, SIRPα generated “don’t eat me” signaling. We also demonstrated that serum inhibited phagocytosis in a SIRPα-dependent manner. Herein, we aimed to determine whether SIRPα-dependent inhibition of phagocytosis in macrophages impedes the in vivo removal of myelin debris in Wallerian degeneration, further leading to impaired healing. Methods Using SIRPα null (SIRPα−/−) and littermate wild-type (SIRPα+/+) mice, we studied the recovery of sensory and motor functions from nerve injury and, further, axon regeneration, SIRPα expression, myelin debris removal, and the phagocytic capacity and presence of macrophages in Wallerian degeneration. Results Myelin debris removal, axon regeneration, and the recovery of functions were all faster in SIRPα−/− mice than in wild-type mice. Between the two cell types that mostly scavenge myelin debris, macrophages but not Schwann cells expressed SIRPα in wild-type mice, and furthermore, SIRPα−/− macrophages phagocytosed significantly more than wild-type macrophages. Conclusions Our findings suggest an intrinsic normally occurring SIRPα-dependent mechanism that impedes the in vivo removal of myelin debris in Wallerian degeneration by inhibiting the phagocytosis of myelin debris in macrophages, hence preventing fast growing axons from fully implementing their regenerative potential. Thus, accelerating the removal of myelin debris by eliminating SIRPα-dependent inhibition of phagocytosis will most likely advance recovery of functions from nerve injury.

Keywords

• SIRPα
• Peripheral nerve
• Nerve injury
• Wallerian degeneration
• Macrophages
• Phagocytosis