Activity of adenosine receptors type 1 is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons
Activity of adenosine receptors type 1 is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons
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DOI：
10.4049/jimmunol.180.11.7590
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Limatola, Cristina
中科院分区：
文献类型：
--
作者：
Lauro, Clotilde;Di Angelantonio, Silvia;Limatola, Cristina
趋化因子fractalkine（CX（3）CL 1）由中枢神经元组成性表达，调节小胶质细胞反应，包括chenrotaxis，激活和毒性。CX（3）CR 1、CX（3）CL 1通过激活其自身的特异性受体，对海马神经元的谷氨酸（Glu）毒性发挥神经保护作用，并对海马神经元的谷氨酸能突触传递进行神经调节。使用从CX（3）CR 1（-/-）（CX（3）CR 1（GFP/GFP））小鼠获得的培养的海马神经元细胞制备物，我们报告通过将神经元暴露于用CX（3）CL 1处理的小鼠小胶质细胞系BV 2（BV 2-st培养基）条件化的培养基来模拟这些相同的作用。此外，CX（3）CL 1诱导的Ght毒性神经保护作用是通过腺苷受体1（AR（1））介导的，被用1，3-二丙基-8-环戊基黄嘌呤（DPCPX）（AR的特异性抑制剂）处理的神经元细胞制剂阻断，并被腺苷和特异性AR激动剂2-氯-N6-环戊基腺苷两者min-ticked。同样，从CX（3）CL 1小鼠获得的培养的全细胞膜片钳海马神经元的实验表明，CX（3）CL 1诱导的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸-（ANVA-）型Ght受体介导电流（AMEPA-电流）的抑制与AR相关，其活性被DPCPX阻断并被腺苷模拟。此外，BV 2-st培养基诱导了CX 3CRIGFPIGFP海马神经元中类似的AMPA电流抑制，并且这种抑制再次被DPCPX阻断。我们还报道了CX（3）CL 1诱导小胶质细胞BV 2细胞显著释放腺苷，如HPLC分析所测量。我们证明：（i）CX（3）CL 1，沿着AR（1），是对抗大脑中Glu介导的神经毒性的关键参与者;（ii）AR（1）介导CX（3）CL 1对海马神经元的神经调节作用。
The chemokine fractalkine (CX(3)CL1) is constitutively expressed by central neurons, regulating microglial responses including chenrotaxis, activation, and toxicity. Through the activation of its own specific receptor, CX(3)CR1, CX(3)CL1 exerts both neuroprotection against glutamate (Glu) toxicity and neuromodulation of the glutamatergic synaptic transmission in hippocampal neurons. Using cultured hippocampal neuronal cell preparations, obtained from CX(3)CR1(-/-) (CX(3)CR1(GFP/GFP)) mice, we report that these same effects are mimicked by exposing neurons to a medium conditioned with CX(3)CL1-treated mouse microglial cell line BV2 (BV2-st medium). Furthermore, CX(3)CL1-induced neuroprotection from Ght toxicity is mediated through the adenosine receptor 1 (AR(1)), being blocked by neuronal cell preparations treatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a specific inhibitor of AR,, and min-ticked by both adenosine and the specific AR, agonist 2-chloro-N6-cyclopentyladenosine. Similarly, experiments from whole-cell patch-clamped hippocampal neurons in culture, obtained from CX(3)CL1 mice, show that CX(3)CL1-induced depression of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- (ANVA-) type Ght receptor-mediated current (AMEPA-current), is associated with AR, activity being blocked by DPCPX and mimicked by adenosine. Furthermore, BV2-st medium induced a similar AMPAcurrent depression in CX3CRIGFPIGFP hippocampal neurons and this depression was again blocked by DPCPX. We also report that CX(3)CL1 induced a significant release of adenosine from microglial BV2 cells, as measured by HPLC analysis. We demonstrate that (i) CX(3)CL1, along with AR(1), are critical players for counteracting Glu-mediated neurotoxicity in the brain and (ii) AR(1) mediates neuromodulatory action of CX(3)CL1 on hippocampal neurons.