Microglial cathepsin B promotes neuronal efferocytosis during brain development

Half of all newborn neurons in the developing brain are removed via efferocytosis - the phagocytic clearance of apoptotic cells. Microglia are brain-resident professional phagocytes that play important roles in neural circuit development including as primary effectors of efferocytosis. While the mechanisms through which microglia recognize potential phagocytic cargo are widely studied, the lysosomal mechanisms that are necessary for efficient digestion are less well defined. Here we show that the lysosomal protease cathepsin B promotes microglial efferocytosis of neurons and restricts the accumulation of apoptotic cells during brain development. We show that cathepsin B is microglia-specific and enriched in brain regions where neuronal turnover is high in both zebrafish and mouse. Myeloid-specific cathepsin B knockdown in zebrafish led to dysmorphic microglia containing undigested dead cells, as well as an accumulation of dead cells in surrounding tissue. These effects where phenocopied in mice globally deficient for