Zhou Yan, Tang Hongmei, Xiong Huangui
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
Department of Pharmacology, Guangxi Medical University, Nanning, Guangxi, People's Republic of China, 530021.
J Neuroimmune Pharmacol. 2016 Jun;11(2):306-15. doi: 10.1007/s11481-016-9660-2. Epub 2016 Mar 11.
Human immunodeficiency virus type 1 (HIV-1)-infected mononuclear phagocytes (brain macrophages and microglial cells) release proinflammatory cytokines and chemokines. Elevated levels of chemokine CC motif ligand 2 (CCL2, known previously as monocyte chemoattractant protein-1) have been detected in serum and cerebrospinal fluid (CSF) of HIV-1-infected individuals and the raised CCL2 in the CSF correlates with HIV-1-associated neurocognitive disorders. To understand how elevated CCL2 induces HIV-1-associated neuropathy, we studied effects of CCL2 on excitatory postsynaptic current (EPSCs) in the CA1 region of rat hippocampal brain slices using whole-cell patch recording techniques. The AMPA receptor (AMPAR)-mediated EPSC (EPSCAMPAR) and N-Methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated EPSCs (EPSCNMDAR) were isolated pharmacologically. Bath application of CCL2 produced a significant enhancement of the amplitudes of EPSCs, EPSCAMPAR and EPSCNMDAR. Further studies revealed that CCL2 potentiated NMDAR subtype NR2A-mediated EPSC (EPSCNR2AR) and NR2B-mediated EPSC (EPSCNR2BR). To determine the site of action, we recorded spontaneous mini EPSCs (mEPSC) before and during bath application of CCL2. Our results showed that CCL2 decreased inter event interval (IEI) and increased the frequency of mEPSCs without change on the amplitude, suggesting a presynaptic site of CCL2 action. CCL2 was also found to injure primary rat hippocampal neuronal cultures and neuronal dendrites in the CA1 region of hippocampal slices. The CCL2-associated neuronal and dendritic injuries were blocked by a specific NMDAR antagonist or by a CCR2 receptor antagonist, indicating that CCL2-associated neural injury was mediated via NMDARs and/or CCR2 receptors. Taken together, these results suggest a potential role CCL2 may play in HIV-1-associated neuropathology.
1型人类免疫缺陷病毒（HIV-1）感染的单核吞噬细胞（脑巨噬细胞和小胶质细胞）会释放促炎细胞因子和趋化因子。在HIV-1感染者的血清和脑脊液（CSF）中已检测到趋化因子CC基序配体2（CCL2，以前称为单核细胞趋化蛋白-1）水平升高，且脑脊液中CCL2升高与HIV-1相关神经认知障碍相关。为了解CCL2水平升高如何诱发HIV-1相关神经病变，我们使用全细胞膜片钳记录技术研究了CCL2对大鼠海马脑片CA1区兴奋性突触后电流（EPSCs）的影响。通过药理学方法分离出α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）介导的EPSC（EPSCAMPAR）和N-甲基-D-天冬氨酸受体（NMDAR）介导的EPSC（EPSCNMDAR）。浴槽应用CCL2可显著增强EPSCs、EPSCAMPAR和EPSCNMDAR的幅度。进一步研究表明，CCL2增强了NMDAR亚型NR2A介导的EPSC（EPSCNR2AR）和NR2B介导的EPSC（EPSCNR2BR）。为确定作用位点，我们在浴槽应用CCL2之前和期间记录了自发性微小EPSC（mEPSC）。我们的结果显示，CCL2减少了事件间隔时间（IEI）并增加了mEPSCs的频率，而幅度没有变化，提示CCL2的作用位点在突触前。还发现CCL2会损伤原代大鼠海马神经元培养物以及海马脑片CA1区的神经元树突。CCL2相关的神经元和树突损伤可被特异性NMDAR拮抗剂或CCR2受体拮抗剂阻断，表明CCL2相关神经损伤是通过NMDARs和/或CCR2受体介导的。综上所述，这些结果提示CCL2在HIV-1相关神经病理学中可能发挥的潜在作用。
