Inhibition of Nav1.8 Transport Promotes Axon Regeneration Via Regulating Dynamic Changes in Macrophage Phenotype after Sciatic Nerve Injury

Abstract

Peripheral nerve injury induces the forward transport of Nav1.8 driven by KIF5b, however, little is known regarding the role of Nav1.8 transport in peripheral nerve regeneration. Here, we reported the beneficial effects of inhibition of Nav1.8 transport on functional recovery and nerve regeneration following experimental sciatic nerve transection (SNT), and characterized the impact of dynamic changes of M1/M2 macrophage polarization phenotypes in this regeneration process. Sequential behavioral data demonstrated a significant improvement of sensory and motor functions over time in rats with inhibition of Nav1.8 transport. Moreover, electrophysiological and histological analysis collectively indicated that inhibition of Nav1.8 transport promoted axonal regrowth after SNT without affecting remyelination of axons. We also discovered that inhibition of Nav1.8 transport facilitates the early recruitment of pro-phagocytic M1 macrophages and subsequently accelerate phenotypic switching from M1 to reparative M2 phenotype, which might be related to the increased secretion of CCL2 and SP acting on macrophage receptor CCR2 and NK-1R respectively. In contrast, enhancing Nav1.8 forward transport by overexpressing KIF5b in DRG neurons substantially impaired the release of CCL2 and SP, the M1/M2 macrophage phenotype switch, and axonal regenerative capacity. Notably, we also found that continuous nerve block with ropivacaine, a non-selective sodium channels blocker, can promote functional recovery and nerve regeneration by inhibiting Nav1.8 transport after SNT. Together, our studies revealed a constructive role of Nav1.8 transport in axonal regrowth after SNT and supported a potential clinical application of continuous blocking with ropivacaine in in peripheral nerve repair.