SYK-dependent lipid handling in monocyte-derived macrophages governs functional recovery after spinal cord injury

After spinal cord injury (SCI), monocyte-derived macrophages and resident microglia play critical, yet potentially distinct, roles in sculpting the lesion milieu via phagocytosis. However, the underlying mechanisms remain unclear. While spleen tyrosine kinase (SYK) has emerged as a master switch for microglial neuroprotection, its function in macrophages after SCI is unknown. Here, we show that SYK expression increases after SCI, peaking at 7 days post-injury (dpi) and persisting until 28 dpi, predominantly within Cx3cr1-GFP^-F4/80⁺ macrophages rather than Cx3cr1-GFP⁺F4/80^- microglia. Pharmacological blockade of SYK with intraperitoneal Entospletinib impaired macrophage phagocytosis, triggered intracellular lipid droplet accumulation, and impeded axonal regrowth and functional recovery. Conversely, SYK agonism with Pustulan injection boosted myelin phagocytosis, accelerated lipid metabolism, and enhanced locomotor outcomes. Notably, in triggering receptor expressed on myeloid cell 2 (TREM2) knockout mice, Pustulan treatment restored macrophage phagocytic competence and lipid droplet clearance, identifying TREM2-SYK signaling as the critical axis governing post-SCI macrophage function. Our findings establish SYK as a therapeutic target for reprogramming macrophage lipid metabolism and promoting repair following SCI.