title: The Complement Receptor C5aR Controls Acute Inflammation and Astrogliosis following Spinal Cord Injury.
abstract: This study investigated the role of the complement activation fragment C5a in secondary pathology following contusive spinal cord injury (SCI). C5ar(-/-) mice, which lack the signaling receptor for C5a, displayed signs of improved locomotor recovery and reduced inflammation during the first week of SCI compared with wild-type mice. Intriguingly, the early signs of improved recovery in C5ar(-/-) mice deteriorated from day 14 onward, with absence of C5aR ultimately leading to poorer functional outcomes, larger lesion volumes, reduced myelin content, and more widespread inflammation at 35 d SCI. Pharmacological blockade of C5aR with a selective antagonist (C5aR-A) during the first 7 d after SCI improved recovery compared with vehicle-treated mice, and this phenotype was sustained up to 35 d after injury. Consistent with observations made in C5ar(-/-) mice, these improvements were, however, lost if C5aR-A administration was continued into the more chronic phase of SCI. Signaling through the C5a-C5aR axis thus appears injurious in the acute period but serves a protective and/or reparative role in the post-acute phase of SCI. Further experiments in bone marrow chimeric mice suggested that the dual and opposing roles of C5aR on SCI outcomes primarily relate to its expression on CNS-resident cells and not infiltrating leukocytes. Additional in vivo and in vitro studies provided direct evidence that C5aR signaling is required during the postacute phase for astrocyte hyperplasia, hypertrophy, and glial scar formation. Collectively, these findings highlight the complexity of the inflammatory response to SCI and emphasize the importance of optimizing the timing of therapeutic interventions.
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
authors.forename: Faith H
authors.initials: FH
authors.lastname: Brennan
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Gordon
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
authors.forename: Hong W
authors.initials: HW
authors.lastname: Lao
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Biggins
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taylor
authors.affiliation: Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute & Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, United Kingdom.
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
authors.forename: Trent M
authors.identifier: http://orcid.org/0000-0003-1382-911X
authors.initials: TM
authors.lastname: Woodruff
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia, Queensland Brain Institute, University of Queensland, Brisbane, 4072, Australia, and Trauma, Critical Care and Recovery, Brisbane Diamantina Health Partners, Brisbane, 4072, Australia m.ruitenberg@uq.edu.au.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Ruitenberg
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology; D015936:Complement C5a / Q000096:biosynthesis; D005260:Female; D005911:Gliosis / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020127:Recovery of Function / Q000502:physiology; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; C570577:hydrocinnamate-(OP(Phe)WR); D015936:Complement C5a
keywords: CNS trauma; anaphylatoxin; demyelinating pathology; macrophage; oligodendrocyte precursor cell; secondary degeneration