Chemokine Fractalkine Attenuates Overactivation and Apoptosis of BV-2 Microglial Cells Induced by Extracellular ATP
Chemokine Fractalkine Attenuates Overactivation and Apoptosis of BV-2 Microglial Cells Induced by Extracellular ATP
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DOI：
10.1007/s11064-013-1010-7
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发表时间：
2013-05-01
影响因子：
4.4
通讯作者：
Li, Ai-Ping
中科院分区：
文献类型：
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作者：
Hao, Fei;Zhang, Nan-Nan;Li, Ai-Ping
小胶质细胞是中枢神经系统(CNS)中驻留的巨噬细胞，由多种信号分子激活，包括兴奋性神经递质三磷酸腺苷(ATP)和具有神经保护和神经毒性作用的神经胶质信号。神经退行性变的“小胶质细胞功能障碍假说”认为，过度激活的小胶质细胞会降低神经保护能力，反而会增加神经毒性。趋化因子Fractalkine(FKN)是仅有的两种趋化因子之一，在多种体内和体外中枢神经系统病理模型中具有神经保护作用。高浓度的ATP可诱导小胶质细胞过度激活和细胞凋亡，而FKN可降低ATP介导的小胶质细胞过度激活和细胞毒作用，这是可能的，但尚未得到证实。在本研究中，我们研究了FKN对三磷酸腺苷诱导的BV-2小胶质细胞株的小胶质细胞凋亡的影响及其可能的机制。暴露于三磷酸腺苷后，BV-2细胞活力呈剂量依赖性下降。长时间暴露于高浓度的ATP(3 mM，2小时)可使分枝(静止)的BV-2细胞进入阿米巴状态，诱导细胞凋亡，并减少Akt的磷酸化。FKN可明显抑制三磷酸腺苷诱导的小胶质细胞凋亡，并使阿米巴小胶质细胞转化为分叉的静止细胞。这些保护作用可被PI3K的化学抑制所阻断，PI3K/Akt信号通路在FKN介导的BV-2细胞对细胞毒性ATP浓度的保护中具有重要意义。阻止ATP诱导的小胶质细胞过度激活和凋亡可能增强这些细胞对急性脑损伤和慢性中枢神经系统疾病的神经保护能力。
Microglia, the resident macrophages of the central nervous system (CNS), are activated by a myriad of signaling molecules including ATP, an excitatory neurotransmitter and neuron-glial signal with both neuroprotective and neurotoxic effects. The "microglial dysfunction hypothesis" of neurodegeneration posits that overactivated microglia have a reduced neuroprotective capacity and instead promote neurotoxicity. The chemokine fractalkine (FKN), one of only two chemokines constitutively expressed in the CNS, is neuroprotective in several in vivo and in vitro models of CNS pathology. It is possible, but not yet demonstrated, that high ATP concentrations induce microglial overactivation and apoptosis while FKN reduces ATP-mediated microglial overactivation and cytotoxicity. In the current study, we examined the effects of FKN on ATP-induced microglial apoptosis and the underlying mechanisms in the BV-2 microglial cell line. Exposure to ATP induced a dose-dependent reduction in BV-2 cell viability. Prolonged exposure to a high ATP concentration (3 mM for 2 h) transformed ramified (quiescent) BV-2 cells to the amoebic state, induced apoptosis, and reduced Akt phosphorylation. Pretreatment with FKN significantly inhibited ATP-induced microglial apoptosis and transformed amoebic microglia to ramified quiescent cells. These protective effects were blocked by chemical inhibition of PI3 K, strongly implicating the PI3 K/Akt signaling pathway in FKN-mediated protection of BV-2 cells from cytotoxic ATP concentrations. Prevention of ATP-induced microglial overactivation and apoptosis may enhance the neuroprotective capacity of these cells against both acute insults and chronic CNS diseases.