CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke.
CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke.
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CX3CR1缺陷抑制实验性缺血性中风中小胶质细胞/巨噬细胞的激活和神经毒性
DOI：
10.1186/1742-2094-11-26
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发表时间：
2014-02-03
影响因子：
9.3
通讯作者：
Shi FD
中科院分区：
文献类型：
--
作者：
Tang Z;Gan Y;Liu Q;Yin JX;Liu Q;Shi J;Shi FD
背景趋化因子（C-X3-C motif）配体1（CX 3CL 1）/CX 3C趋化因子受体1（CX 3CR 1）信号转导在调节中枢神经系统（CNS）内神经元与驻留的小胶质细胞/迁移的巨噬细胞之间的通讯中起重要作用。虽然CX 3CR 1缺陷与缺血性脑损伤后的预后改善有关，但这一观察结果的机制在很大程度上尚不清楚。本研究的目的是探讨CX 3CR 1缺陷如何影响小胶质细胞/巨噬细胞功能的背景下，其保护以下脑ischemia.MethodsWild-type（WT）和CX 3CR 1缺陷（CX 3CR 1-/-）小鼠进行短暂的大脑中动脉闭塞（MCAO）和再灌注。通过啮齿动物高场磁共振成像监测缺血性脑损伤。每天评估神经功能缺损。通过免疫染色和活体成像分析神经元凋亡和活性氧（ROS）的产生。采用免疫组化、流式细胞术、5-溴-2-脱氧尿苷标记、细胞因子ELISA和实时荧光PCR等方法检测CX 3CR 1-/-小鼠MCAO后小胶质细胞/巨噬细胞的活化/炎症反应。此外，CX 3CR 1-/-MCAO小鼠表现出更少的凋亡神经元和降低的ROS水平。CX 3CR 1信号通路受损可抑制外周血单核细胞源性巨噬细胞的募集，抑制CNS小胶质细胞和浸润巨噬细胞的增殖，促进替代激活（M2状态）的小胶质细胞/巨噬细胞，并减弱其合成和释放炎性cytokines.ConclusionOur结果表明，抑制CX 3CR 1信号转导可以作为缺血性脑损伤的治疗方式，通过减少外周巨噬细胞的募集以及CNS小胶质细胞和巨噬细胞的扩增/活化，从而保护神经功能。
BackgroundChemokine (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.MethodsWild-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.ResultsCX3CR1-/-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.ConclusionOur 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.
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DOI：
10.1523/jneurosci.4403-10.2010
发表时间：
2010-12-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Liu Z;Condello C;Schain A;Harb R;Grutzendler J
通讯作者：
Grutzendler J
DOI：
10.1073/pnas.95.18.10896
发表时间：
1998-09-01
影响因子：
11.1
作者：
Harrison, JK;Jiang, Y;Feng, LL
通讯作者：
Feng, LL
影响因子：
82.9
作者：
Liesz, Arthur;Suri-Payer, Elisabeth;Veltkamp, Roland
通讯作者：
Veltkamp, Roland
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG