Macrophage Targeting Protects Nerve Structure and Improves Muscle Innervation in a Mouse Model of Charcot-Marie-Tooth 2J.

In several previous studies, we have shown that macrophage targeting with the CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 led to a substantial alleviation of the neuropathy in distinct mouse models of demyelinating Charcot-Marie-Tooth (CMT) 1 forms. However, whether macrophages are also relevant drivers of the neuropathy in axonal CMT2 subtypes has not been studied so far. Here, we investigated the role of macrophages in hemizygous P0T124M mice, which develop a late-onset axonopathy accompanied by macrophage activation at 18 months of age and reflect typical pathological signs of a CMT2J neuropathy. As a tool to target macrophages before disease onset, hemizygous P0T124M mice were treated with PLX5622 from 12 to 18 months of age. Remarkably, treatment with PLX5622 not only ameliorated the peripheral neuropathy to an exceptionally high degree but also prevented distal axonal degeneration and denervation of neuromuscular junctions, leading to preserved motor function in CMT2J mice. These findings highlight macrophage-mediated inflammation as a treatment target in peripheral nerves not only in previously investigated demyelinating but also in axonal CMT neuropathies.