Neuregulin-1 facilitates myelin regeneration through microglia-mediated mechanisms in a mouse model of chronic demyelination

Impaired myelin repair, or remyelination, is a hallmark of progressive multiple sclerosis (MS) that drives brain degeneration and enduring neurological disabilities. Microglia crucially support remyelination through myelin phagocytosis and lipid metabolism. However, in chronic demyelinated MS lesions, microglia lose their reparative function by acquiring a foamy dysfunctional phenotype characterized by accumulation of lipid droplets due to impaired cholesterol processing of myelin debris. Here, we show a positive correlation between dysregulation of neuregulin-1 and impaired oligodendrocyte remyelination in mice with chronic demyelination. Therapeutic restoration of neuregulin-1 fosters myelin regeneration through microglia-dependent mechanisms. We demonstrate that Nrg-1 signaling supports microglia integrity and function in chronic demyelinated lesions by exploiting their capacity for the clearance of myelin debris and cholesterol recycling, biosynthesis and efflux. These findings signify the promise of neuregulin-1 as an endogenous target to facilitate microglia mediated-repair in progressive MS in which there is an unmet need for new treatments. Dysfunction of microglia in lipid processing after myelin phagocytosis contributes to the impaired remyelination in progressive multiple sclerosis. Here, the authors link depletion of neuregulin-1 in chronic demyelinated lesions to microglia foaminess that can be reversed therapeutically to promote remyelination in mice.