CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents
CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents
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DOI：
10.1523/jneurosci.3611-11.2011
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发表时间：
2011-11-09
影响因子：
5.3
通讯作者：
Limatola, Cristina
中科院分区：
文献类型：
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作者：
Cipriani, Raffaela;Villa, Pia;Limatola, Cristina
趋化因子CX 3CL 1及其受体CX 3CR 1在神经系统中组成型表达。在这项研究中，我们在体内永久性大脑中动脉闭塞（pMCAO）的小鼠模型，研究CX 3CL 1的保护潜力。我们报告外源性CX 3CL 1减少缺血诱导的脑梗死面积，神经功能缺损和caspase-3激活。CX 3CL 1诱导的神经保护作用是持久的，在大鼠pMCAO后观察到长达50天。CX 3CL 1在不同脑损伤模型中的神经保护作用是通过其对小胶质细胞的抑制活性介导的，并且在体外需要腺苷受体1（A（1）R）的激活。我们发现，在A1 R拮抗剂1，3-二丙基-8-环戊基黄嘌呤存在下，在A（1）R（-/-）小鼠中，CX 3CL 1对pMCAO的神经保护作用被消除，表明腺苷系统在CX 3CL 1保护中也是至关重要的。与上述报道的数据明显相反，但与先前的发现一致，分别缺乏CX 3CL 1或CX 3CR 1的cx 3cl 1（-/-）和cx 3cr 1（GFP/GFP）小鼠在pMCAO上具有较不严重的脑损伤，并且外源性CX 3CL 1的施用增加了cx 3cl 1（-/-）缺血小鼠的脑损伤。我们还报告，CX 3CL 1诱导不同的吞噬活性在野生型和cx 3CL 1（-/-）小胶质细胞在体外与条件培养基中损伤的氧葡萄糖剥夺。总之，这些数据表明，CX 3CL 1的急性给药通过腺苷依赖性机制减少缺血性损伤，并且组成性CX 3CL 1-CX 3CR 1信号传导的缺乏改变了CX 3CL 1给药至缺血性脑期间小胶质细胞介导的作用的结果。
The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used in vivo murine models of permanent middle cerebral artery occlusion (pMCAO) to investigate the protective potential of CX3CL1. We report that exogenous CX3CL1 reduced ischemia-induced cerebral infarct size, neurological deficits, and caspase-3 activation. CX3CL1-induced neuroprotective effects were long lasting, being observed up to 50 d after pMCAO in rats. The neuroprotective action of CX3CL1 in different models of brain injuries is mediated by its inhibitory activity on microglia and, in vitro, requires the activation of adenosine receptor 1 (A(1)R). We show that, in the presence of the A1R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in A(1)R(-/-) mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also in vivo. In apparent contrast with the above reported data but in agreement with previous findings, cx3cl1(-/-) and cx3cr1(GFP/GFP) mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in cx3cl1(-/-) ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and cx3cl1(-/-) microglia in vitro during cotreatment with the medium conditioned by neurons damaged by oxygenglucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosinedependent mechanism and that the absence of constitutive CX3CL1-CX3CR1 signaling changes the outcome of microglia- mediated effects during CX3CL1 administration to ischemic brain.