Microglial handling of myelin debris and remyelination after ischaemic stroke: recognition, intracellular processing, lipid fate, and oligodendroglial repair.

Abstract

Post-ischaemic white-matter injury involves axonal dysfunction, myelin disorganization, delayed accumulation of myelin-derived debris, and an often incomplete regenerative response. Microglia provide a cellular link between debris clearance and white-matter repair through a sequence of functionally distinct processes encompassing selective debris recognition, internalization, intracellular degradation, lipid handling, inflammatory regulation, and oligodendroglial support. Importantly, increased myelin uptake should not be equated with successful clearance, and clearance itself does not establish effective remyelination. This review prioritizes direct evidence from adult ischaemic stroke while using studies from related white-matter and demyelination models to clarify defined cellular or metabolic steps as mechanistic context rather than as stroke-equivalent evidence. Available evidence indicates that OPC recruitment and early lineage responses are frequently preserved after stroke, whereas terminal oligodendrocyte maturation and structurally competent myelin reconstruction remain limiting steps. Within microglia, lysosomal competence and post-phagocytic lipid processing emerge as critical intermediate bottlenecks that determine whether internalized myelin is successfully disposed of or instead promotes lipid accumulation, inflammatory dysfunction, and impaired oligodendroglial support. Direct adult-stroke evidence nevertheless remains substantially more limited than the broader mechanistic literature derived from related experimental systems. We therefore propose that repair-relevant microglial activity should be evaluated across sequential checkpoints-from selective recognition and intracellular processing to lipid disposal, oligodendroglial maturation, and structurally and functionally validated remyelination.