Microglial phagocytosis of single dying oligodendrocytes is mediated by CX3CR1 but not MERTK.

Oligodendrocyte death is common in aging and neurodegenerative diseases. In these conditions, single dying oligodendrocytes must be efficiently removed to allow remyelination and prevent a feed-forward degenerative cascade. Here we used a single-cell cortical demyelination model combined with longitudinal intravital imaging of dual-labeled transgenic mice to investigate the cellular dynamics underlying how brain resident microglia remove these cellular debris. Following phagocytic engagement, single microglia cleared the targeted oligodendrocyte and its myelin sheaths in one day via a precise, rapid, and stereotyped sequence. Deletion of the fractalkine receptor, CX3CR1, delayed microglia engagement with the cell soma but unexpectedly did not affect the clearance of myelin sheaths. Furthermore, and in contrast to previous reports in other demyelination models, deletion of the phosphatidylserine receptor, MERTK, did not affect oligodendrocyte or myelin sheath clearance. Thus, distinct molecular signals are used to detect, engage, and clear sub-compartments of dying oligodendrocytes to maintain tissue homeostasis.