Multifaceted involvement of microglia in gray matter pathology in multiple sclerosis

In the inflammatory demyelinating neurodegenerative disease multiple sclerosis (MS), there is increasing interest in gray matter pathology, as neuronal loss and cortical atrophy correlate with disability and disease progression, and MS therapeutics fail to significantly slow or stop neurodegeneration. Microglia, the central nervous system (CNS)-resident macrophages, are extensively involved in white matter MS pathology, but are also implicated in gray matter pathology, similar to other neurodegenerative diseases, for which there is synaptic, axonal, and neuronal degeneration. Microglia display regional heterogeneity within the CNS, which reflects their highly plastic nature and their ability to deliver context-dependent responses tailored to the demands of their microenvironment. Therefore, microglial roles in the MS gray matter in part reflect and in part diverge from those in the white matter. The present review summarizes current knowledge of microglial involvement in gray matter changes in MS, in demyelination, synaptic damage, and neurodegeneration, with evidence implicating microglia in pathology, neuroprotection, and repair. As our understanding of microglial physiology and pathophysiology increases, we describe how we are moving toward potential therapeutic applications in MS, harnessing microglia to protect and regenerate the CNS.