CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke

Journal of Neuroinflammation

Fu-Dong Shi¹  Jiong Shi²  Qingwei Liu²  Jun-Xiang Yin²  Qiang Liu¹  Yan Gan²  Zhiwei Tang³ 

[1] Department of Neurology, Key Laboratory of Neurorepair and Regeneration, Tianjin and Ministry of Education and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China;Department of Neurology and the BNI-ASU Center for Preclinical Imaging, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, 350 West Thomas Road, Phoenix, Arizona 85013, USA;Department of Neurosurgery, the First Affiliated Hospital of Kunming Medical University, Kunming 650031, China

关键词: Middle cerebral artery occlusion;    Ischemic stroke;    Macrophage;    Microglia;    CX3CR1^-/-;   

Others  :  824839
DOI  :  10.1186/1742-2094-11-26

 received in 2013-08-01, accepted in 2014-01-13,  发布年份 2014

【 摘 要 】

Background

Chemokine (C-X3-C motif) ligand 1 (CX3CL1)/ CX3C chemokine receptor 1 (CX3CR1) signaling is important in modulating the communication between neurons and resident microglia/migrated macrophages in the central nervous system (CNS). Although CX3CR1 deficiency is associated with an improved outcome following ischemic brain injury, the mechanism of this observation is largely unknown. The aim of this study was to investigate how CX3CR1 deficiency influences microglia/macrophage functions in the context of its protection following brain ischemia.

Methods

Wild-type (WT) and CX3CR1-deficient (CX3CR1^-/-) mice were subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion. The ischemic brain damage was monitored by rodent high-field magnetic resonance imaging. Neurological deficit was assessed daily. Neuronal apoptotic death and reactive oxygen species (ROS) production were analyzed by immunostaining and live imaging. Activation/inflammatory response of microglia/macrophage were assessed using immunohistochemistry, flow cytometry, 5-bromo-2-deoxyuridine labeling, cytokine ELISA, and real-time PCR.

Results

CX3CR1^-/- mice displayed significantly smaller infarcts and less severe neurological deficits compared to WT controls, following MCAO. In addition, CX3CR1^-/- MCAO mice displayed fewer apoptotic neurons and reduced ROS levels. Impaired CX3CR1 signaling abrogated the recruitment of monocyte-derived macrophages from the periphery, suppressed the proliferation of CNS microglia and infiltrated macrophage, facilitated the alternative activation (M2 state) of microglia/macrophages, and attenuated their ability to synthesize and release inflammatory cytokines.

Conclusion

Our results suggest that inhibition of CX3CR1 signaling could function as a therapeutic modality in ischemic brain injury, by reducing recruitment of peripheral macrophages and expansion/activation of CNS microglia and macrophages, resulting in protection of neurological function.

【 授权许可】

   
2014 Tang et al.; licensee BioMed Central Ltd.

【 图 表 】

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