Microglia promote remyelination independent of their role in clearing myelin debris

Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss. While therapies exist to slow MS progression, no treatment currently exists for remyelination. Remyelination, linked to reduced disability in MS, relies on microglia and monocyte-derived macrophages (MDMs). This study aims to understand the role of microglia during remyelination by lineage tracing and depleting them. Microglial lineage tracing reveals that both microglia and MDMs initially accumulate, but microglia later dominate the lesion. Microglia and MDMs engulf equal amounts of inhibitory myelin debris, but after microglial depletion, MDMs compensate by engulfing more myelin debris. Microglial depletion does, however, reduce the recruitment and proliferation of oligodendrocyte progenitor cells (OPCs) and impairs their subsequent differentiation and remyelination. These findings underscore the essential role of microglia during remyelination and offer insights for enhancing this process by understanding microglial regulation of remyelination. [Display omitted] •Microglia and monocyte-derived macrophages engulf equal volumes of myelin debris•Macrophages compensate to remove myelin debris when microglia are depleted•Microglia facilitate oligodendrocyte progenitor cell proliferation•Microglia promote oligodendrocyte differentiation and remyelination Baaklini et al. demonstrate that, after demyelination, microglia and monocyte-derived macrophages engulf equal volumes of myelin debris. They found that microglia depletion did not impact myelin debris clearance because monocyte-derived macrophages could compensate. They found that microglia did promote oligodendrocyte progenitor cell recruitment and their subsequent differentiation and remyelination.