Multiple sclerosis (MS) is the most common autoimmune and demyelinating disease of the central nervous system (CNS), characterized, in the majority of cases, by initial relapses that later evolve into progressive neurodegeneration, severely impacting patients’ motor and cognitive functions. Despite the availability of immunomodulatory therapies effective to reduce relapse rate and slow disease progression, they all failed to restore CNS myelin that is necessary for MS full recovery. Microglia are the primary inflammatory cells present in MS lesions, therefore strongly contributing to demyelination and lesion extension. Thus, many microglial-based therapeutic strategies have been focused on the suppression of microglial pro-inflammatory phenotype and neurodegenerative state to reduce disease severity. On the other hand, the contribution of myelin phagocytosis advocating the neuroprotective role of microglia in MS has been less explored. Indeed, despite the presence of functional oligodendrocyte precursor cells (OPCs), within lesioned areas, MS plaques fail to remyelinate as a result of the over-accumulation of myelin-toxic debris that must be cleared away by microglia. Dysregulation of this process has been associated with the impaired neuronal recovery and deficient remyelination. In line with this, here we provide a comprehensive review of microglial myelin phagocytosis and its involvement in MS development and repair. Alongside, we discuss the potential of phagocytic-mediated therapeutic approaches and encourage their modulation as a novel and rational approach to ameliorate MS-associated pathology.
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