The Alternative Receptor for Complement Component 5a, C5aR2, Conveys Neuroprotection in Traumatic Spinal Cord Injury.
This study investigated the role of the alternative receptor for complement activation fragment C5a, C5aR2, in secondary inflammatory pathology after contusive spinal cord injury (SCI) in mice. C5ar2-/-mice exhibited decreased intraparenchymal tumor necrosis factor alpha and interleukin-6 acutely post-injury, but these reductions did not translate into improved outcomes. We show that loss of C5aR2 leads to increased lesion volumes, reduced myelin sparing, and significantly worsened recovery from SCI in C5ar2-/-animals compared to wild-type (WT) controls. Loss of C5aR2 did not alter leukocyte mobilization from the bone marrow in response to SCI, and neutrophil recruitment/presence at the lesion site was also not different between genotypes. Acute treatment of SCI mice with the selective C5aR1 antagonist, PMX205, improved SCI outcomes, compared to vehicle controls, and, importantly, fully alleviated the worsened recovery of C5ar2-/-mice compared to their WT counterparts. Collectively, these findings indicate that C5aR2 is neuroprotective and a novel target to restrain injurious C5a signaling after a major neurotraumatic event.
1 School of Biomedical Sciences, The University of Queensland , Brisbane, Australia .
Patrick J C
PJC
Biggins
1 School of Biomedical Sciences, The University of Queensland , Brisbane, Australia .
Faith H
FH
Brennan
1 School of Biomedical Sciences, The University of Queensland , Brisbane, Australia .
Stephen M
SM
Taylor
1 School of Biomedical Sciences, The University of Queensland , Brisbane, Australia .
Trent M
TM
Woodruff
1 School of Biomedical Sciences, The University of Queensland , Brisbane, Australia .|2 Queensland Brain Institute, The University of Queensland , Brisbane, Australia .|3 Trauma, Critical Care and Recovery, Brisbane Diamantina Health Partners , Brisbane, Australia .
Marc J
MJ
Ruitenberg
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000066829:Neuroprotection; D010456:Peptides, Cyclic / Q000494:pharmacology; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*
C000591759:C5ar1 protein, mouse; C000594938:C5ar2 protein, mouse; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; C504156:hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)
degeneration; inflammation; neural injury; secondary insult; traumatic spinal cord injury