CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation

Journal of Neuroinflammation

Hong Zhou²  Meiqing Shi¹  Mingshun Zhang²  Xingxing Zhu²  Dongyan Shi²  Tian Jiao²  Yawei Zhao²  Fengjiao Wu² 

[1] Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, Maryland 20742, MD, USA;Department of Immunology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, JS, China

关键词: Intravital microscopy;    Leukocyte recruitment;    Endothelial activation;    Astrocyte;    CXCR2;    CXCL1;    CNS inflammation;   

Others  :  1221988
DOI  :  10.1186/s12974-015-0316-6

 received in 2015-03-09, accepted in 2015-04-30,  发布年份 2015

【 摘 要 】

Background

Chemokines 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.

Methods

Wild-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.

Results

Expression 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.

Conclusions

CXCL1 secreted by astrocytes and endothelial CXCR2 play essential roles in cerebral endothelial activation and subsequent leukocyte recruitment during neuroinflammation.

【 授权许可】

   
2015 Wu et al.; licensee BioMed Central.

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