Effects of C3 deficiency on inflammation and regeneration following spinal cord injury in mice

Abstract

Inflammation can activate the complement system, which in turn enhances inflammation and aggravates secondary injury after spinal cord injury (SCI). As the three complement activation pathways converge at the cleavage of C3, we investigated whether inhibiting complement activation in C3-deficient mice would reduce secondary injury after SCI and improve axon regeneration. Weight-drop contusion injury (5 g, 6 cm) was created in wild-type or C3-deficient mice. Astrocytes (ASTs) activation, TNF-α expression, and axon regeneration were investigated in vivo. In other studies, dorsal root ganglia (DRGs) were co-cultured with mechanically injured ASTs in vitro to evaluate effects on neurite outgrowth. Our results show that, after injury, C3-deficient mice exhibit higher BBB scores than wild-type mice. In addition, ASTs activation was inhibited, TNF-α expression process was delayed in vivo and inhibited in vitro, and nerve fiber regeneration was improved in C3-deficient mice. DRGs co-cultured with mechanically injured ASTs from C3-deficient mice also showed improved neurite outgrowth. We conclude that C3 deficiency can inhibit inflammation through suppressing ASTs activation and TNF-α expression, thereby reducing secondary injury and improving neural regeneration and functional recovery after SCI. The above results suggest that complement inhibition may be a potential therapy to promote central nervous system regeneration by targeting C3.