A role for complement in the pathophysiology and recovery of function following contusion-induced spinal cord injury

The complement system is instrumental in host defense, mediating innate immune functions and regulating adaptive immune responses. This system consists of more than 30 plasma and membrane-bound proteins. Circulating complement proteins are mainly synthesized by hepatocytes and circulate in the bloodstream, however complement proteins are also synthesized by peripheral blood leukocytes and CNS cells. Complement activation results in the generation of opsonic fragments (C3b & C4b), anaphylactic fragments (C3a and C5a) and formation of membrane attack complex (C5b-9). The complement system is an effective mechanism for eliminating foreign pathogens, however, accumulating evidence suggests that it may mediate both beneficial and detrimental functions in the central nervous system (CNS). Although the complement system has received considerable attention in injury and disease models of the brain, much less attention has been directed at investigating the complement system in animal models of spinal cord injury (SCI).;To investigate the role of the classical and terminal complement pathways in SCI, we acquired C1q KO mice, C6 deficient mice and C6 deficient rats. C6 deficient rodents lack the ability to form the membrane attack complex (C5b-9). C1q KO mice and C6-deficient mice were backcrossed onto the BUB/BnJ mouse strain because while rats appear to exhibit the same degree of total complement hemolytic activity as humans, the majority of common mouse strains are constitutively deficient in this activity with the exception of the BUB/BnJ mouse strain. To test the hypothesis that complement is detrimental to recovery following SCI, animals received a mild/moderate contusion injury at thoracic level 9 with the Infinite Horizon Impactor. Preliminary investigations of the terminal complement pathway revealed that PVG C6 deficient rats showed greater locomotor recovery, greater white matter sparing and reduced macrophage infiltration. Critically, investigations of the classical complement pathway demonstrated that BUB C1q knockout mice exhibited improved behavioral recovery and reduced lesion volume compared to BUB wildtype mice. In contrast, BUB C6 deficient mice showed greater behavioral deficits and less remyelination than BUB WT mice. While our preliminary observations in C6 deficient rats support the long-standing view that C5b-9 contributes to central nervous system pathology, the experimental paradigm in mice is appreciably genetically controlled and is the first study to formally test the hypothesis that C5b-9 contributes to CNS neuropathology. In conclusion these studies suggest that the classical and terminal complement pathway play critical yet divergent roles in SCI.;...