Macrophages influence Schwann cell myelin autophagy after nerve injury and in a model of Charcot-Marie-Tooth disease

Abstract

Background and aims: The complex cellular and molecular interactions between Schwann cells (SCs) and macrophages during Wallerian degeneration are a prerequisite to allow rapid uptake and degradation of myelin debris and axonal regeneration after peripheral nerve injury. In contrast, in non-injured nerves of Charcot-Marie-Tooth 1 neuropathies, aberrant macrophage activation by SCs carrying myelin gene defects is a disease amplifier that drives nerve damage and subsequent functional decline. Consequently, targeting nerve macrophages might be a translatable treatment strategy to mitigate disease outcome in CMT1 patients. Indeed, in previous approaches, macrophage targeting alleviated the axonopathy and promoted sprouting of damaged fibers. Surprisingly, this was still accompanied by robust myelinopathy in a model for CMT1X, suggesting additional cellular mechanisms of myelin degradation in mutant peripheral nerves. We here investigated the possibility of an increased SC-related myelin autophagy upon macrophage targeting in Cx32def mice.

Methods: Combining ex vivo and in vivo approaches, macrophages were targeted by PLX5622 treatment. SC autophagy was investigated by immunohistochemical and electron microscopical techniques.

Results: We demonstrate a robust upregulation of markers for SC autophagy after injury and in genetically-mediated neuropathy when nerve macrophages are pharmacologically depleted. Corroborating these findings, we provide ultrastructural evidence for increased SC myelin autophagy upon treatment in vivo.

Interpretation: These findings reveal a novel communication and interaction between SCs and macrophages. This identification of alternative pathways of myelin degradation may have important implications for a better understanding of therapeutic mechanisms of pharmacological macrophage targeting in diseased peripheral nerves.

Keywords: Schwann cell autophagy; Wallerian degeneration; colony stimulating factor 1 receptor inhibitor; inherited peripheral neuropathy; macrophage; neuroinflammation.