Depleting non-resolving neuroinflammation in chronic spinal cord injury attenuates thermal hypersensitivity.

Macrophage and microglial densities around spinal cord injury (SCI) lesions remain chronically elevated. The influence of non-resolving neuroinflammation on ongoing functions, repair, or regeneration after SCI is not well understood. We administered a 2-week treatment of the CSF1-R antagonist, PLX-5622 (PLX), to deplete inflammatory microglia/macrophages (Iba-1+-cells) within and around chronic contusion SCI lesions starting after 9-weeks post-injury and evaluated changes in locomotor functions and thermal hypersensitivity. Spinal cord sections were assessed for axon growth within the lesion and spared tissue compartments around the injury as well as in the grey matter caudal to the injury. Flow cytometry was performed to evaluate the influence of PLX on both microglia and macrophage populations within the spinal cord. While PLX significantly depleted Iba-1+ cells both around and within the lesion, flow cytometry revealed no measurable depletion of macrophage populations but validated a depletion effect on microglia. Iba-1+-cell depletion with PLX reduced locomotor abilities by the end of the 2-week treatment period without exacerbating the lesion pathology. Motor abilities remained decreased relative to pre-treatment levels after allowing for Iba-1+-cell repopulation by removal of PLX. Inflammatory depletion resolved thermal hypersensitivity which remained resolved after inflammatory repopulation. CGRP+ axons were significantly elevated in chronic contusive lesions after Iba-1+-cell repopulation, but no CGRP+ axon sprouting was observed below the lesion. Collectively our work supports a role of chronic neuroinflammation as an ongoing regulator of motor and sensory behaviors after SCI. SIGNIFICANCE STATEMENT: Elevated macrophage and microglial densities persist around chronic spinal cord injury (SCI) lesions for life and very little is understood about their ongoing contributions to repair or function. Our work identifies that non-resolving neuroinflammation plays an active role in producing neuropathic pain and impeding endogenous repair that can be ameliorated by depleting macrophages and microglia from the spinal cord at chronic timepoints. Our work provides a novel perspective on the nature of chronic neuroinflammation after SCI as it relates to ongoing motor and sensory functions as well as axon growth.