CD300f enables microglial damage sensing, efferocytosis, and apoptotic cell metabolization after brain injury.

Microglia, the resident phagocytes of the central nervous system (CNS), continuously survey the parenchyma and its borders, acting as first responders to brain injury. Their ability to detect and react to environmental changes is mediated by a repertoire of surface receptors collectively known as themicroglial sensome. Here, we identify the lipid-sensing immunoreceptor CD300f as a key regulator of microglial responses to tissue damage and apoptotic cells. Using intravital two-photon microscopy, we show that CD300f microglia fail to extend processes toward a laser-induced cortical lesion, indicating impaired detection of damage-associated cues. In models of mild traumatic brain injury (mTBI) and intracortical injection of apoptotic cells, CD300f deficiency led to reduced recognition and clearance of dying cells resulting in the accumulation of cellular debris within the parenchyma. At later stages, apoptotic remnants were retained within CD300f microglia in vivo and bone marrow-derived macrophages in vitro, suggesting defective intracellular degradation. Proteomic analysis after a controlled cortical injury (CCI) contusion model revealed widespread dysregulation of autophagy-related and metabolic pathways, consistent with impaired efferocytosis and phagolysosomal processing. In parallel, we observed upregulation of the UDP-degrading ectonucleotidase ENTPD6 protein and downregulation of the microglial purinergic receptor P2ry6 mRNA, indicating a dysfunctional UDP-P2RY6 axis that may underlie impaired damage sensing and phagocytic initiation. Despite greater histological preservation, CD300f mice exhibited worse long-term functional recovery after brain injury. Together, these findings highlight CD300f as a key damage-associated molecular pattern (DAMP) receptor that integrates purinergic signaling, efferocytosis, and metabolic adaptation, highlighting its essential role in coordinating microglial responses to CNS injury.