CD300f immune receptor is a microglial tissue damage sensor and regulates efferocytosis after brain damage

Microglia, the resident phagocytes of the central nervous system (CNS), continuously monitor the parenchyma and surrounding borders and are the primary responders to brain damage. CD300f is a lipid-sensing immunoreceptor present in the microglial cell membrane, which binds to phosphatidylserine and other lipid mediators. Defining the functional microglial sensome is critical to understand their function and cell state determination. Using intravital two-photon microscopy we show that microglia lacking the CD300f receptor fail to detect environmental damage cues after a laser ablation injury. After a mild traumatic brain injury or after the intracortical injection of apoptotic cells, CD300f ^-/- microglia showed reduced capacity for detecting and phagocytosing dyeing cells, leading to the accumulation of dead cells in the neural parenchyma. Moreover, at later timepoints, increased accumulation of dyeing cells was found inside CD300f ^-/- microglia in vivo and in bone marrow-derived macrophages in vitro, suggesting that these cells display a reduced capacity for metabolizing phagocytosed cells. Finally, CD300f deficiency increased functional compromise after a contusive traumatic brain injury, associated to increased conservation of brain tissue. Collectively, these results suggest that CD300f function as a damage-associated molecular pattern (DAMP) receptor that coordinates microglial process reaction towards tissue debris and highlights its central role in microglial sensome machinery and in the modulation of in vivo microglial efferocytosis.