Microglia are implicated in all stages ofmultiple sclerosis (MS). Microglia alterations are detected by positron emission tomography in people living with MS prior to the formation of structural lesions determined through magnetic resonance imaging. In histological specimens, clusters of microglia form in normal-appearing tissue likely predating the development of lesions. Features of degeneration-associated/pro-inflammatory states of microglia increase with chronicity of MS. However, microglia play many beneficial roles including the removal of neurotoxins and in fostering repair. The protector-gone-rogue microglia in MS is featured herein. We consider mechanisms of microglia neurotoxicity and discuss factors, including aging, osteopontin, and iron metabolism, that cause microglia to lose their protective states and become injurious. We evaluate medications to affect microglia in MS, such as the emerging class of Bruton's tyrosine kinase inhibitors. The framework of microglia- turned-destroyers may instigate new approaches to counter microglia-driven neurodegeneration in MS.
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