title: Deficiency of complement receptors CR2/CR1 in Cr2⁻/⁻ mice reduces the extent of secondary brain damage after closed head injury.
abstract: Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury.
authors.forename: Miriam D
authors.initials: MD
authors.lastname: Neher
authors.forename: Megan C
authors.initials: MC
authors.lastname: Rich
authors.forename: Chesleigh N
authors.initials: CN
authors.lastname: Keene
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weckbach
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Bolden
authors.forename: Justin T
authors.initials: JT
authors.lastname: Losacco
authors.forename: Jenée
authors.initials: J
authors.lastname: Patane
authors.forename: Michael A
authors.initials: MA
authors.lastname: Flierl
authors.forename: Liudmila
authors.initials: L
authors.lastname: Kulik
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.affiliation: Department of Orthopedic Surgery, Denver Health Medical Center, University of Colorado School of Medicine, 777 Bannock Street, Denver CO 80204, USA. philip.stahel@dhha.org.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Stahel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003176:Complement C3 / Q000378:metabolism; D006259:Craniocerebral Trauma / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007075:Immunoglobulin M / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000097:blood; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000172:deficiency*; D017464:Receptors, Complement 3d / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D003176:Complement C3; D018398:Homeodomain Proteins; D007075:Immunoglobulin M; D019253:Proto-Oncogene Proteins c-bcl-2; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d; D019014:fas Receptor; C064658:RAG-1 protein; D010751:Phosphopyruvate Hydratase