Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival
Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival
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DOI：
10.1073/pnas.090017497
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发表时间：
2000-07-05
影响因子：
11.1
通讯作者：
Miller, RJ
中科院分区：
文献类型：
--
作者：
Meucci, O;Fatatis, A;Miller, RJ
最近的体外和体内研究表明，趋化因子fractalkine在脑中广泛表达，主要定位于神经元。CX（3）CR 1是Fractalkine唯一已知的受体，其在中枢神经系统的表达仅在小胶质细胞和星形胶质细胞中得到证实。因此，有人提出，fractalkine调节神经元（产生fractalkine）和小胶质细胞（表达其受体）之间的细胞通讯。在这里，我们首次发现海马神经元也表达CX（3）CR 1。通过可溶性fractalkine的受体活化诱导蛋白激酶Akt（促存活信号传导途径的主要组分）的活化和NF-κ B（Akt的下游效应物）的核转位。Fractalkine保护海马神经元免受HIV-1包膜蛋白gp 120（IIIB）诱导的神经毒性，抗CX（3）CR 1抗体阻断了这种作用。使用Akt激活中的关键酶磷脂酰肌醇3-激酶的两种不同抑制剂和Akt磷脂激活剂的实验表明，Akt激活是Fractalkine神经保护作用的原因。这些数据表明，神经元CX（3）CR 1受体介导fractalkine的神经营养作用，表明fractalkine及其受体参与了神经元和胶质细胞之间的旁分泌和自分泌相互作用的复杂网络。
Recent in vitro and in vivo studies have shown that the chemokine fractalkine is widely expressed in the brain and localized principally to neurons. Central nervous system expression of CX(3)CR1, the only known receptor for fractalkine, has been demonstrated exclusively on microglia and astrocytes. Thus, it has been proposed that fractalkine regulates cellular communication between neurons (that produce fractalkine) and microglia (that express its receptor). Here we show, for the first time, that hippocampal neurons also express CX(3)CR1. Receptor activation by soluble fractalkine induces activation of the protein kinase Akt, a major component of prosurvival signaling pathways, and nuclear translocation of NF-KB, a downstream effector of Akt. Fractalkine protects hippocampal neurons from the neurotoxicity induced by the HIV-1 envelope protein gp120(IIIB), an effect blocked by anti-CX(3)CR1 antibodies, Experiments with two different inhibitors of the phosphatidylinositol 3-kinase, a key enzyme in the activation of Akt, and with a phospholipid activator of Akt demonstrate that Akt activation is responsible for the neuroprotective effects of fractalkine. These data show that neuronal CX(3)CR1 receptors mediate the neurotrophic effects of fractalkine, suggesting that fractalkine and its receptor are involved in a complex network of both paracrine and autocrine interactions between neurons and glia.