Cytosolic phospholipase A2 regulates alcohol-mediated astrocyte inflammatory responses in HIV-associated neurocognitive disorders.
Cytosolic phospholipase A2 regulates alcohol-mediated astrocyte inflammatory responses in HIV-associated neurocognitive disorders.
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DOI：
10.1038/cddiscovery.2015.45
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发表时间：
2015
影响因子：
7
通讯作者：
Ghorpade A
中科院分区：
文献类型：
--
作者：
Pandey R;Ghorpade A
酒精滥用和HIV-1感染不仅在美国，而且在全世界仍然是主要的公共卫生问题。在全球范围内，酗酒者感染艾滋病毒-1的风险明显高于不饮酒者。在美国，EtOH滥用的流行率在hiv -1阳性个体中是普通人群的两倍多。尽管酒精滥用者表现出神经退行性变、神经炎症加剧和氧化损伤，但EtOH在hiv相关神经认知障碍中调节星形胶质细胞炎症反应的机制尚不清楚。因此，我们探索了etoh介导的人类星形细胞HIV-1激活及其随后炎症功能改变的信号通路。酒精暴露以剂量依赖的方式改变了星形胶质细胞的形态、促炎反应和诱导的细胞毒性。还评估了随时间变化的变化。EtOH和HIV-1共处理降低了细胞活力和增殖，同时增加了细胞凋亡和线粒体去极化。EtOH和HIV-1共同增加了促炎分子、白细胞介素-1β、肿瘤坏死因子-α、CXCL8、金属蛋白酶组织抑制剂-1的水平，更重要的是，花生四烯酸（已知的胞质磷脂酶A2 （cPLA2）的下游靶点）的水平。与这一观察结果一致，与单独治疗HIV-1或EtOH相比，HIV-1和EtOH共治疗时磷酸- cpla2水平升高。通过实时PCR和western blot检测，环氧化酶2上调，而与单独使用EtOH相比，HIV-1和EtOH共处理降低了细胞色素P450-2E1水平。此外，我们证实了用花生四烯基三氟甲基酮（一种cPLA2特异性抑制剂）阻断cPLA2，有效地阻止了cPLA2的磷酸化和下游结果。因此，目前的研究结果表明，cPLA2在酒精和hiv诱导的星形胶质细胞炎症中起关键作用。在未来，cPLA2抑制剂可能会提供新的治疗工具来治疗酒精滥用和hiv相关的神经认知障碍合并症。
Alcohol (EtOH) abuse and HIV-1 infection remain leading public health problems not only in the United States but also across the world. Alcohol abusers have a significantly greater risk of HIV-1 infection than non-drinkers globally. In the United States, prevalence of EtOH abuse is over two-fold higher in HIV-1-positive individuals than that of the general population. Although alcohol abusers show neurodegeneration, exacerbated neuroinflammation and oxidative damage, the mechanism(s) by which EtOH regulates astrocyte inflammatory responses in HIV-associated neurocognitive disorders is unknown. Thus, we explored signaling pathway(s) involved in EtOH-mediated activation of human astrocytes with HIV-1 and subsequent alterations in their inflammatory functions. Alcohol exposure altered the morphology of astrocytes, proinflammatory responses and induced cytotoxicity in a dose-dependent manner. Time-dependent changes were also evaluated. EtOH and HIV-1 cotreatment decreased cell viability and proliferation, while increasing apoptosis and mitochondrial depolarization. EtOH and HIV-1 together increased the levels of proinflammatory molecules, interleukin-1β, tumor necrosis factor-α, CXCL8, tissue inhibitor of metalloproteinases-1 and more importantly, arachidonic acid, a known downstream target of cytosolic phospholipase A2 (cPLA2). Consistent with this observation, phospho-cPLA2 levels were augmented in HIV-1 and EtOH cotreatment as compared with HIV-1 or EtOH alone. Cyclooxygenase 2 was upregulated as measured by real-time PCR and western blot, whereas cotreatment of HIV-1 and EtOH decreased cytochrome P450-2E1 levels as compared with EtOH alone. Furthermore, we confirmed that blocking cPLA2 with arachidonyl tri floro methyl ketone, a cPLA2-specific inhibitor, effectively prevented cPLA2 phosphorylation and downstream outcomes. Thus, the present findings suggest that cPLA2 has a critical role in alcohol and HIV-induced astrocyte inflammation. In the future, cPLA2 inhibitors may present novel therapeutic tools to treat alcohol abuse and HIV-associated neurocognitive disorder comorbidity.