Spinal cord microglia exhibit a dysfunctional response to myelin damage

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that affects both the brain and spinal cord, although the brain has historically received greater attention. In the inducible, oligodendrocyte-specific knockout model of Myrf, which results in white matter damage to both the brain and spinal cord, our laboratory previously demonstrated that the brain undergoes remyelination following white matter damage, whereas the spinal cord has limited remyelination. We also observed that brain microglia display a much stronger activation than spinal cord microglia. Microglia regulate remyelination by clearing myelin debris, processing resulting lipids, and modulating the inflammation response. Therefore, we hypothesized that microglia are involved in limiting spinal cord remyelination in this model, either by having a limited phagocytosis response or by causing neuroinflammation. To test our hypothesis, we characterized microglial phenotypes during demyelination in both brain and spinal cord in the Myrf demyelination model. The brain exhibited an earlier microglial activation response and showed a higher percentage of microglia expressing phagocytic markers, suggesting a primed state for responding to damage. In contrast, spinal cord microglia showed a delayed increase in cells expressing phagocytic markers, sustained inflammation, and a predominately ameboid morphology during demyelination. Together, these findings in the Myrf demyelination model indicate that brain microglia mount a timely and coordinated response to demyelination that supports remyelination, whereas spinal cord microglia adopt a dysfunctional phenotype that likely contributes to reduced myelin repair.