title: Complement-dependent P-selectin expression and injury following ischemic stroke.
abstract: The mechanisms that contribute to inflammatory damage following ischemic stroke are poorly characterized, but studies indicate a role for both complement and P-selectin. In this study, we show that compared with wild-type mice, C3-deficient mice showed significant improvement in survival, neurological deficit, and infarct size at 24 h after middle cerebral artery occlusion and reperfusion. Furthermore, P-selectin protein expression was undetectable in the cerebral microvasculature of C3-deficient mice following reperfusion, and there was reduced neutrophil influx, reduced microthrombus formation, and increased blood flow postreperfusion in C3-deficient mice. We further investigated the use of a novel complement inhibitory protein in a therapeutic paradigm. Complement receptor 2 (CR2)-Crry inhibits complement activation at the C3 stage and targets to sites of complement activation. Treatment of normal mice with CR2-Crry at 30 min postreperfusion resulted in a similar level of protection to that seen in C3-deficient mice in all of the above-measured parameters. The data demonstrate an important role for complement in cerebrovascular thrombosis, inflammation, and injury following ischemic stroke. P-selectin expression in the cerebrovasculature, which is also implicated in cerebral ischemia and reperfusion injury, was shown to be distal to and dependent on complement activation. Data also show that a CR2-targeted approach of complement inhibition provides appropriate bioavailability in cerebral injury to enable complement inhibition at a dose that does not significantly affect systemic levels of serum complement activity, a potential benefit for stroke patients where immunosuppression would be undesirable due to significantly increased susceptibility to lung infection.
authors.affiliation: Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Fei
authors.initials: F
authors.lastname: Qiao
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Varela
authors.forename: Jin
authors.initials: J
authors.lastname: Yu
authors.forename: Hongbin
authors.initials: H
authors.lastname: Song
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kindy
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002545:Brain Ischemia / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D002560:Cerebrovascular Circulation / Q000276:immunology; D003176:Complement C3 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003169:Complement Inactivator Proteins / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D019007:P-Selectin / Q000096:biosynthesis* / Q000502:physiology; D011951:Receptors, Complement / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D016019:Survival Analysis
chemical_list: D003176:Complement C3; D003169:Complement Inactivator Proteins; C081470:Cr1l protein, mouse; D019007:P-Selectin; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d