CXCL8 as a Potential Therapeutic Target for HIV-Associated Neurocognitive Disorders.
CXCL8 as a Potential Therapeutic Target for HIV-Associated Neurocognitive Disorders.
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DOI：
10.2174/1389450116666150626124544
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发表时间：
2015-12
影响因子：
3.2
通讯作者：
Manmeet K. Mamik;A. Ghorpade
中科院分区：
文献类型：
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作者：
Manmeet K. Mamik;A. Ghorpade
趋化因子CXCL8是一种低分子量的中性粒细胞趋化剂，与各种神经退行性疾病包括阿尔茨海默病和中风有关。据报道，CXCL8在人类免疫缺陷病毒(HIV)-1感染的神经认知障碍患者的血清、血浆和脑中表达增加，表明其在与HIV-1脑感染相关的神经炎症中起作用。由于趋化因子在引发中枢神经系统（CNS）的免疫反应中起着至关重要的作用，CXCL8作为第一个在大脑中被描述的趋化因子之一，具有特别重要的意义。星形胶质细胞和小胶质细胞被HIV-1和病毒相关蛋白激活导致脑微环境中这种趋化因子的产生。因此，CXCL8通过g蛋白偶联受体CXCR1和CXCR2作用于靶细胞。中性粒细胞是CXCL8的主要靶细胞；然而，小胶质细胞和神经元也表达CXCR1/CXCR2，因此是cxcl8介导的串扰的重要靶点。这篇综述的目的是关注CXCL8在神经元和神经胶质细胞中对HIV-1感染的产生、信号传导和调控。我们强调了HIV-1分泌蛋白如转录反式激活因子、包膜糖蛋白、负调节因子和病毒蛋白r在CXCL8调控中的作用。我们讨论了CXCL8在神经退行性变和中枢神经系统神经保护中的双重作用。因此，通过开发基于CXCR1/ cxcr2的治疗策略，靶向CXCL8选择性地激活或拮抗受体，可能能够选择性地促进神经保护和抗炎结果，从而在许多神经炎症性中枢神经系统疾病（包括hiv相关的神经认知障碍）中具有重要的临床应用。
Chemokine CXCL8 is a low molecular weight neutrophil chemoattractant implicated in various neurodegenerative disorders including Alzheimer's disease and stroke. Increased expression of CXCL8 has been reported in serum, plasma and brain of human immunodeficiency virus (HIV)-1 infected individuals with neurocognitive impairment, indicating its role in neuroinflammation associated with HIV-1 infection of the brain. Since chemokines are critical in eliciting immune responses in the central nervous system (CNS), CXCL8 is of particular importance for being one of the first chemokines described in the brain. Activation of astrocytes and microglia by HIV-1 and virus associated proteins results in production of this chemokine in the brain microenvironment. Consequently, CXCL8 exerts its effect on target cells via Gprotein coupled receptors CXCR1 and CXCR2. Neutrophils are the main target cells for CXCL8; however, microglia and neurons also express CXCR1/CXCR2 and therefore are important targets for CXCL8-mediated crosstalk. The objective of this review is to focus on CXCL8 production, signaling and regulation in neuronal and glial cells in response to HIV-1 infection. We highlight the role of HIV-1 secreted proteins such as trans-activator of transcription, envelope glycoprotein, negative regulatory factor and viral protein r in the regulation of CXCL8. We discuss dual role of CXCL8 in neurodegeneration as well as neuroprotection in the CNS. Thus, targeting CXCL8 through the development of CXCR1/CXCR2-based therapeutic strategies to either selectively agonize or antagonize receptors may be able to selectively promote neuroprotective and anti-inflammatory outcomes, leading to significant clinical applications in many neuroinflammatory CNS diseases, including HIV-associated neurocognitive disorders.