Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction

Microglia are the principal phagocytes that clear cell debris in the central nervous system (CNS). This raises the question, which cells remove cell debris when microglial phagocytic activity is impaired. We addressed this question usingSiglech(dtr)mice, which enable highly specific ablation of microglia. Non-microglial mononuclear phagocytes, such asCNS-associated macrophages and circulating inflammatory monocytes, did not clear microglial debris. Instead, astrocytes were activated, exhibited a pro-inflammatory gene expression profile, and extended their processes to engulf microglial debris. This astrocytic phagocytosis was also observed inIrf8-deficient mice, in which microglia were present but dysfunctional.RNA-seq demonstrated that even in a healthyCNS, astrocytes expressTAMphagocytic receptors, which were the main astrocytic phagocytic receptors for cell debris in the above experiments, indicating that astrocytes stand by in case of microglial impairment. This compensatory mechanism may be important for the maintenance or prolongation of a healthyCNS.