Lipid accumulation in foam cells drives C1q-dependent synaptic loss and impairs motor function recovery after spinal cord injury

Macrophages play a critical role in the repair process following spinal cord injury (SCI), yet the complex mechanisms underlying their functionality remain poorly understood. Using single-cell RNA sequencing, we identified distinct macrophage subpopulations post-SCI, with lipid-laden macrophages, or foam cells, representing the terminal differentiation stage and persisting throughout the chronic phase. Our findings reveal that foam cells display increased expression of C1q, a complement component, which thereby activates microglial phagocytosis of synapses adjacent to the lesion site. This process results in synaptic loss, impairing motor function recovery in SCI mice. Through high-content screening, we identified bazedoxifene as a potential therapeutic candidate that significantly attenuates lipid droplet accumulation within foam cells. This reduction in lipid load diminishes C1q expression by foam cells, thereby mitigating synaptic pathology and promoting synaptic preservation near the injury site. Our findings establish a novel connection between lipid metabolism and C1q-dependent synaptic damage, providing new insights into the mechanisms by which macrophages hinder functional recovery after SCI.