The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury.
Complement is implicated in the inflammatory response and the secondary neuronal damage that occurs after traumatic spinal cord injury (SCI). Complement can be activated by the classical, lectin, or alternative pathways, all of which share a common terminal pathway that culminates in formation of the cytolytic membrane attack complex (MAC). Here, we investigated the role of the alternative and terminal complement pathways in SCI. Mice deficient in the alternative pathway protein factor B (fB) were protected from traumatic SCI in terms of reduced tissue damage and demyelination, reduced inflammatory cell infiltrate, and improved functional recovery. In a clinically relevant paradigm, treatment of mice with an anti-fB mAb resulted in similarly improved outcomes. These improvements were associated with decreased C3 and fB deposition. On the other hand, deficiency of CD59, an inhibitor of the membrane attack complex, resulted in significantly increased injury and impaired functional recovery compared to wild-type mice. Increased injury in CD59-deficient mice was associated with increased MAC deposition, while levels of C3 and fB were unaffected. These data indicate key roles for the alternative and terminal complement pathways in the pathophysiology of SCI. Considering a previous study demonstrating an important role for the classical pathway in promoting SCI, it is likely that the alternative pathway plays a critical role in amplifying classical pathway initiated complement activation.
Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
Fei
F
Qiao
Carl
C
Atkinson
Mark S
MS
Kindy
Anandakumar
A
Shunmugavel
B Paul
BP
Morgan
Hongbin
H
Song
Stephen
S
Tomlinson
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology / Q000502:physiology; D003167:Complement Activation / Q000502:physiology; D003170:Complement Pathway, Alternative / Q000502:physiology*; D003171:Complement Pathway, Classical / Q000502:physiology*; D003711:Demyelinating Diseases / Q000209:etiology / Q000473:pathology; D005260:Female; D008124:Locomotion / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009187:Myelitis / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000534:rehabilitation; D009504:Neutrophils / Q000473:pathology; D020127:Recovery of Function / Q000502:physiology; D013119:Spinal Cord Injuries / Q000150:complications / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000534:rehabilitation