Reduced tissue damage and improved recovery of motor function after traumatic brain injury in mice deficient in complement component C4.
Complement component C4 mediates C3-dependent tissue damage after systemic ischemia-reperfusion injury. Activation of C3 also contributes to the pathogenesis of experimental and human traumatic brain injury (TBI); however, few data exist regarding the specific pathways (classic, alternative, and lectin) involved. Using complement knockout mice and a controlled cortical impact (CCI) model, we tested the hypothesis that the classic pathway mediates secondary damage after TBI. After CCI, C4c and C3d immunostaining were detected in cortical vascular endothelial cells in wild-type (WT) mice; however, C4c and C3d immunostaining were also detected in C1q(-/-) mice, and C3d immunostaining was detected in C4(-/-) mice. After CCI, WT and C1q(-/-) mice had similar motor deficits, Morris water maze performance, and brain lesion size. Naive C4(-/-) and WT mice did not differ in baseline motor performance, but C4(-/-) mice had reduced postinjury motor deficits (days 1 to 7, P<0.05) and decreased brain tissue damage (days 14 and 35, P<0.05) versus WT. Reconstitution of C4(-/-) mice with human C4 (hC4) reversed their protection against postinjury motor deficits (P<0.05 versus vehicle), but administration of hC4 did not impair postinjury motor performance (versus vehicle) in WT mice. The protective effects of C4(-/-) were functionally distinct from the classic pathway and terminal complement, as C1q(-/-) and C3(-/-) mice had postinjury tissue damage and motor dysfunction similar to WT. Thus, C4 contributes to motor deficits and brain tissue damage after CCI by mechanism(s) fundamentally different from those involved in experimental systemic ischemia-reperfusion injury.
You
Zerong
Z
Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Yang
Jinsheng
J
Takahashi
Kazue
K
Yager
Phoebe H
PH
Kim
Hyung-Hwan
HH
Qin
Tao
T
Stahl
Gregory L
GL
Ezekowitz
R Alan B
RA
Carroll
Michael C
MC
Whalen
Michael J
MJ
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001929:Brain Edema / Q000235:genetics / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D003181:Complement C4 / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009068:Movement / Q000502:physiology*; D011597:Psychomotor Performance / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D003181:Complement C4