title: The alternative complement pathway propagates inflammation and injury in murine ischemic stroke.
abstract: There is mounting evidence indicating an important role for complement in the pathogenesis of cerebral ischemia-reperfusion injury, or ischemic stroke. The role of the alternative complement pathway in ischemic stroke has not been investigated, and there is conflicting data on the role of the terminal pathway. In this study, we show that compared with wild-type mice, mice deficient in the alternative pathway protein factor B or mice treated with the alternative pathway inhibitor CR2-fH have improved outcomes after 60-min middle cerebral artery occlusion and 24-h reperfusion. Factor B-deficient or CR2-fH-treated mice were protected in terms of improved neurologic function and reduced cerebral infarct, demyelination, P-selectin expression, neutrophil infiltration, and microthrombi formation. Mice deficient in both the classical and lectin pathways (C1q/MBL deficient) were also protected from cerebral ischemia-reperfusion injury, and there was no detectable C3d deposition in the ipsilateral brain of these mice. These data demonstrate that the alternative pathway is not alone sufficient to initiate complement activation and indicate that the alternative pathway propagates cerebral injury via amplification of the cascade. Deficiency of C6, a component of the terminal cytolytic membrane attack complex, had no effect on outcome after ischemic stroke, indicating that the membrane attack complex is not involved in mediating injury in this model. We additionally show that the protective effect of factor B deficiency and CR2-fH treatment is sustained in the subacute stage of infarct development, adding to the clinical relevance of these findings.
authors.affiliation: Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Elvington
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Jin
authors.initials: J
authors.lastname: Yu
authors.forename: Kazue
authors.initials: K
authors.lastname: Takahashi
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Stahl
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kindy
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018957:CD59 Antigens / Q000235:genetics; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics; D003183:Complement C6 / Q000172:deficiency / Q000235:genetics; D011415:Complement Factor B / Q000172:deficiency / Q000235:genetics; D015938:Complement Membrane Attack Complex / Q000172:deficiency / Q000235:genetics; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000235:genetics; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D020521:Stroke / Q000235:genetics / Q000276:immunology* / Q000473:pathology*
chemical_list: D018957:CD59 Antigens; C539311:CD59a protein, mouse; D003183:Complement C6; D015938:Complement Membrane Attack Complex; D018836:Inflammation Mediators; D015922:Complement C1q; D011415:Complement Factor B