title: Complement component C3a plays a critical role in endothelial activation and leukocyte recruitment into the brain.
abstract: BACKGROUND
  The complement system is becoming increasingly recognized as a key participant in many neurodegenerative diseases of the brain. Complement-deficient animals exhibit reduced neuroinflammation.
  
  
  METHODS
  In the present study, we administered intracerebroventricularly lipopolysaccharide (LPS) to mimic local infection of the brain and investigated the role of key complement component C3 in brain vasculature endothelial activation and leukocyte recruitment. The degree of neutrophil infiltration was determined by esterase staining. Leukocyte-endothelial interactions were measured using intravital microscopy. Cerebral endothelial activation was evaluated using real-time PCR and Western blotting.
  
  
  RESULTS
  Neutrophil infiltration into the brain cortex and hippocampus was significantly reduced in C3(-/-) mice and C3aR(-/-) mice but not in C6(-/-) mice. We detected markedly attenuated leukocyte-endothelial interactions in the brain microvasculature of C3(-/-) mice. Accordingly, in response to LPS administration, the brain microvasculature in these mice had decreased expression of P-selectin, E-selectin, intercellular cell adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). Depletion of C3 from the circulation also caused reduction in VCAM-1 and E-selectin expression and leukocyte recruitment, suggesting that C3 in the circulation contributed to brain endothelial activation. Furthermore, C3(-/-) mice exhibited decreased leukocyte recruitment into the brain upon tumor necrosis factor-α (TNF-α) stimulation. C3a activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) and induced the upregulation of VCAM-1 and ICAM-1 expression in murine primary cerebral endothelial cells in vitro.
  
  
  CONCLUSIONS
  Our study provides the first evidence that C3a plays a critical role in cerebral endothelial activation and leukocyte recruitment during inflammation in the brain.
authors.affiliation: Department of Immunology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, JS, 210029, China. 124914924@qq.com.
authors.forename: Fengjiao
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu, 610083, Sichuan, China. qiangzou99@gmail.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zou
authors.affiliation: Department of Immunology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, JS, 210029, China. xdding@sibs.ac.cn.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Immunology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, JS, 210029, China. shidongyan1984@hotmail.com.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Shi
authors.affiliation: Department of Immunology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, JS, 210029, China. 809418148@qq.com.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Shanghai Cancer Center and Institute of Biomedical Science, Shanghai Medical College, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. weiguohu@fudan.edu.cn.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5, Canada. lixin.liu@usask.ca.
authors.forename: Lixin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Immunology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, JS, 210029, China. hzhou@njmu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015926:Complement C3a / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007276:Injections, Intraventricular; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics; D013997:Time Factors
chemical_list: D015815:Cell Adhesion Molecules; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a
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