The role of microglia in remyelination: Mechanisms and therapeutic implications in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system, accompanied by progressive neurological deficits. Current MS disease-modifying drugs mainly target peripheral immune cells and have demonstrated little efficacy for neuroprotection or remyelination. Growing evidence indicates that microglia play a critical dual role in demyelinating animal models and MS. In acute inflammatory phases, microglia adopt a pro-inflammatory phenotype, exacerbating demyelination and neural damage. But, as lesions evolve, these resident immune cells can transform into an anti-inflammatory state, promoting tissue repair and myelin regeneration. Despite the importance of microglia, the regulatory mechanism of this double-edged sword during demyelination and remyelination has not been fully elucidated. This review first provides an overview of the involvement of microglia in demyelination and remyelination, and how their functional evolution depends on disease stage, on the spatial location of the lesion and its microenvironment. Secondly, the interaction between microglia and astrocytes, monocyte-derived macrophages, T cells, and B cells is described, working together to balance the disrupted microenvironment, promote the formation, differentiation, and maturation of oligodendrocyte precursor cells, and ultimately achieve myelin protection and regeneration. We then organize the signaling pathways targeting microglia and remyelination, providing a theoretical basis for drug development. Finally, we present drugs or small-molecule compounds targeting signaling pathways for exploratory therapeutic research at different stages. In summary, this review highlights the importance of remyelination, microglial heterogeneity, the temporal nature of regulation, and the complexity of treatment. We also present some challenges and solutions for remyelination, providing valuable information for neurological recovery in MS patients.