Complement component C3a plays a critical role in endothelial activation and leukocyte recruitment into the brain.
Complement component C3a plays a critical role in endothelial activation and leukocyte recruitment into the brain.
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补体成分 C3a 在内皮激活和白细胞募集到大脑中发挥着关键作用
DOI：
10.1186/s12974-016-0485-y
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发表时间：
2016-01-28
影响因子：
9.3
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Wu F;Zou Q;Ding X;Shi D;Zhu X;Hu W;Liu L;Zhou H
背景补体系统越来越被认为是许多脑神经退行性疾病的关键参与者。补体缺乏的动物表现出减少neuroniflammation.MethodsIn本研究中，我们给药脑室内脂多糖（LPS）模拟局部感染的大脑和研究的作用，脑血管内皮细胞活化和白细胞招聘的关键补体成分C3。中性粒细胞浸润的程度通过酯酶染色来确定。使用活体显微镜测量白细胞-内皮相互作用。大脑内皮细胞活化进行了评估，使用实时PCR和Western blotting. ResultsNeurons浸润到大脑皮层和海马在C3−/−小鼠和C3 aR −/−小鼠，但不是在C6−/−小鼠显着减少。我们在C3−/−小鼠的脑微血管中检测到明显减弱的白细胞-内皮细胞相互作用。因此，响应于LPS给药，这些小鼠的脑微血管系统中P-选择素、E-选择素、细胞间细胞粘附分子1（ICAM-1）和血管细胞粘附分子1（VCAM-1）的表达降低。循环中C3的消耗也引起VCAM-1和E-选择素表达和白细胞募集的减少，表明循环中的C3有助于脑内皮激活。此外，C3−/−小鼠在肿瘤坏死因子-α（TNF-α）刺激后表现出脑内白细胞募集减少。C3 a激活p38丝裂原活化蛋白激酶（MAPK）和核因子-κB（NF-κB B）的磷酸化，并诱导VCAM-1和ICAM-1在小鼠原代脑内皮细胞中的表达上调。
BackgroundThe complement system is becoming increasingly recognized as a key participant in many neurodegenerative diseases of the brain. Complement-deficient animals exhibit reduced neuroinflammation.MethodsIn 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.ResultsNeutrophil 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.ConclusionsOur study provides the first evidence that C3a plays a critical role in cerebral endothelial activation and leukocyte recruitment during inflammation in the brain.