CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation
CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation
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DOI：
10.1186/s12974-015-0316-6
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发表时间：
2015-05
影响因子：
9.3
通讯作者：
Fengjiao Wu;Yawei Zhao;Tian Jiao;D. Shi;Xingxing Zhu;Mingshun Zhang;M. Shi;Hong Zhou
中科院分区：
文献类型：
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作者：
Fengjiao Wu;Yawei Zhao;Tian Jiao;D. Shi;Xingxing Zhu;Mingshun Zhang;M. Shi;Hong Zhou
背景趋化因子和趋化因子受体协同作用促进免疫细胞向中枢神经系统（CNS）募集.在这项研究中，我们调查的作用CXCR2和CXCL1在白细胞募集到中枢神经系统使用小鼠模型neuroniflations.MethodsWild-type（WT），CXCL1-/-，和CXCR2-/-小鼠分别接受脑室内（i.c.v.）注射脂多糖（LPS）。进行酯酶染色和活体显微镜检查，以检查中性粒细胞向大脑的募集。为了评估这些小鼠的内皮活化，通过定量实时聚合酶链反应（PCR）和蛋白质印迹法测量粘附分子的表达。为了确定功能CXCR2的细胞来源，嵌合体小鼠通过转移骨髓细胞之间的WT和CXCR2 −/− mice. ResultsExpression趋化因子CXCL1，CXCL2和CXCL5的表达水平显着增加，在脑内注射LPS。CXCR2或CXCL1缺乏阻断了中性粒细胞浸润和白细胞在脑微血管中募集。在CXCR2 −/−和CXCL1 −/−小鼠中，粘附分子如P-选择素和VCAM-1的脑内皮表达显著降低。此外，骨髓移植实验表明，CXCR2在CNS驻留细胞上的表达对于脑内皮活化和白细胞募集是必需的。与小胶质细胞相比，体外培养的星形胶质细胞分泌更高水平的CXCL 1。星形胶质细胞条件培养液可显著增加脑血管内皮细胞VCAM-1和ICAM-1的表达，且呈CXCR2依赖性。此外，肿瘤坏死因子-α（TNF-α）刺激后，脑内皮细胞中CXCR2信使RNA（mRNA）表达增加，但小胶质细胞或星形胶质细胞中未增加。结论星形胶质细胞分泌的CXCL1和内皮细胞CXCR2在神经炎症过程中对脑内皮细胞活化和白细胞募集起重要作用。
BackgroundChemokines and chemokine receptors cooperate to promote immune cell recruitment to the central nervous system (CNS). In this study, we investigated the roles of CXCR2 and CXCL1 in leukocyte recruitment to the CNS using a murine model of neuroinflammation.MethodsWild-type (WT), CXCL1−/−, and CXCR2−/−mice each received an intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS). Esterase staining and intravital microscopy were performed to examine neutrophil recruitment to the brain. To assess endothelial activation in these mice, the expression of adhesion molecules was measured via quantitative real-time polymerase chain reaction (PCR) and Western blotting. To identify the cellular source of functional CXCR2, chimeric mice were generated by transferring bone marrow cells between the WT and CXCR2−/−mice.ResultsExpression levels of the chemokines CXCL1, CXCL2, and CXCL5 were significantly increased in the brain following the i.c.v. injection of LPS. CXCR2 or CXCL1 deficiency blocked neutrophil infiltration and leukocyte recruitment in the cerebral microvessels. In the CXCR2−/−and CXCL1−/−mice, the cerebral endothelial expression of adhesion molecules such as P-selectin and VCAM-1 was dramatically reduced. Furthermore, the bone marrow transfer experiments demonstrated that CXCR2 expression on CNS-residing cells is essential for cerebral endothelial activation and leukocyte recruitment. Compared with microglia, cultured astrocytes secreted a much higher level of CXCL1 in vitro. Astrocyte culture conditioned medium significantly increased the expression of VCAM-1 and ICAM-1 in cerebral endothelial cells in a CXCR2-dependent manner. Additionally, CXCR2 messenger RNA (mRNA) expression in cerebral endothelial cells but not in microglia or astrocytes was increased following tumor necrosis factor-α (TNF-α) stimulation. The intravenous injection of the CXCR2 antagonist SB225002 significantly inhibited endothelial activation and leukocyte recruitment to cerebral microvessels.ConclusionsCXCL1 secreted by astrocytes and endothelial CXCR2 play essential roles in cerebral endothelial activation and subsequent leukocyte recruitment during neuroinflammation.