Microglia in multiple sclerosis: pathogenesis and therapeutic modulation

Background  Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination, neuroinflammation, axonal injury, and progressive neurodegeneration. Microglia, the resident innate immune cells of the brain, are central participants in these processes and act as both effectors of tissue injury and mediators of repair. Objective  To critically synthesize current neuroimmunological evidence on the role of microglia in the initiation, propagation, and partial resolution of MS pathology, with particular emphasis on demyelination, axonal injury, remyelination failure, and cognitive dysfunction, and to evaluate the therapeutic potential of targeted modulation of microglial phenotype, phagocytic capacity, and immunometabolic signaling. Methods  Analytical narrative review of contemporary peer-reviewed literature (2005–2026) on microglial biology in MS, with priority given to single-cell transcriptomic studies, mechanistic preclinical work, and recent clinical trials of microglia-modulating therapies, including brain-penetrant Bruton tyrosine kinase (BTK) inhibitors. Results  Microglia in MS exhibit substantial transcriptional and functional heterogeneity. Disease-associated states such as “microglia inflamed in MS” (MIMS) and iron-laden rim microglia of chronic active lesions sustain compartmentalized neuroinflammation and contribute to slow expansion of lesions and progressive disability. Concurrently, microglial phagocytosis of myelin debris through TREM2, MerTK, CR3, and scavenger receptors is essential for oligodendrocyte precursor maturation and remyelination. Excess intracellular myelin lipid load can convert reparative microglia into a dysfunctional, foam-like proinflammatory phenotype. Therapeutic modulation of microglia — including brain-penetrant BTK inhibition, TREM2 agonism, complement modulation, and immunometabolic interventions — has produced encouraging preclinical data and, most recently, positive phase 3 clinical evidence in non-relapsing secondary progressive MS. Conclusion  Microglia are central to both tissue injury and tissue repair in MS. Selective modulation of microglial function — rather than indiscriminate suppression — represents a biologically rational and clinically emerging strategy for limiting chronic neuroinflammation, supporting remyelination, and addressing disability progression that current peripherally-acting disease-modifying therapies leave unmet. Keywords  multiple sclerosis; microglia; demyelination; neuroinflammation; phagocytosis; remyelination; disease-associated microglia; TREM2; Bruton tyrosine kinase inhibitor; chronic active lesion