Coley Jacqueline S, Calderon Tina M, Gaskill Peter J, Eugenin Eliseo A, Berman Joan W
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America.
PLoS One. 2015 Feb 3;10(2):e0117450. doi: 10.1371/journal.pone.0117450. eCollection 2015.
Drug abuse is a major comorbidity of HIV infection and cognitive disorders are often more severe in the drug abusing HIV infected population. CD14+CD16+ monocytes, a mature subpopulation of peripheral blood monocytes, are key mediators of HIV neuropathogenesis. Infected CD14+CD16+ monocyte transmigration across the blood brain barrier mediates HIV entry into the brain and establishes a viral reservoir within the CNS. Despite successful antiretroviral therapy, continued influx of CD14+CD16+ monocytes, both infected and uninfected, contributes to chronic neuroinflammation and the development of HIV associated neurocognitive disorders (HAND). Drug abuse increases extracellular dopamine in the CNS. Once in the brain, CD14+CD16+ monocytes can be exposed to extracellular dopamine due to drug abuse. The direct effects of dopamine on CD14+CD16+ monocytes and their contribution to HIV neuropathogenesis are not known. In this study, we showed that CD14+CD16+ monocytes express mRNA for all five dopamine receptors by qRT-PCR and D1R, D5R and D4R surface protein by flow cytometry. Dopamine and the D1-like dopamine receptor agonist, SKF38393, increased CD14+CD16+ monocyte migration that was characterized as chemokinesis. To determine whether dopamine affected cell motility and adhesion, live cell imaging was used to monitor the accumulation of CD14+CD16+ monocytes on the surface of a tissue culture dish. Dopamine increased the number and the rate at which CD14+CD16+ monocytes in suspension settled to the dish surface. In a spreading assay, dopamine increased the area of CD14+CD16+ monocytes during the early stages of cell adhesion. In addition, adhesion assays showed that the overall total number of adherent CD14+CD16+ monocytes increased in the presence of dopamine. These data suggest that elevated extracellular dopamine in the CNS of HIV infected drug abusers contributes to HIV neuropathogenesis by increasing the accumulation of CD14+CD16+ monocytes in dopamine rich brain regions.
药物滥用是HIV感染的一种主要合并症，并且在滥用药物的HIV感染者中认知障碍往往更为严重。CD14+CD16+单核细胞是外周血单核细胞的一个成熟亚群，是HIV神经发病机制的关键介质。受感染的CD14+CD16+单核细胞穿越血脑屏障介导HIV进入大脑，并在中枢神经系统内建立病毒储存库。尽管抗逆转录病毒疗法取得了成功，但受感染和未受感染的CD14+CD16+单核细胞持续流入，会导致慢性神经炎症以及HIV相关神经认知障碍（HAND）的发展。药物滥用会增加中枢神经系统中的细胞外多巴胺。一旦进入大脑，由于药物滥用，CD14+CD16+单核细胞可能会接触到细胞外多巴胺。多巴胺对CD14+CD16+单核细胞的直接影响及其对HIV神经发病机制的作用尚不清楚。在本研究中，我们通过定量逆转录聚合酶链反应（qRT-PCR）表明CD14+CD16+单核细胞表达所有五种多巴胺受体的信使核糖核酸（mRNA），并通过流式细胞术检测到D1R、D5R和D4R表面蛋白。多巴胺和D1样多巴胺受体激动剂SKF38393增加了CD14+CD16+单核细胞的迁移，其特征为化学运动。为了确定多巴胺是否影响细胞运动性和黏附，使用活细胞成像来监测CD14+CD16+单核细胞在组织培养皿表面的聚集情况。多巴胺增加了悬浮的CD14+CD16+单核细胞沉降到培养皿表面的数量和速率。在铺展试验中，多巴胺在细胞黏附的早期阶段增加了CD14+CD16+单核细胞的面积。此外，黏附试验表明，在多巴胺存在的情况下，黏附的CD14+CD16+单核细胞的总数总体增加。这些数据表明，HIV感染的药物滥用者中枢神经系统中细胞外多巴胺水平升高，通过增加富含多巴胺的脑区中CD14+CD16+单核细胞的积累，促进了HIV神经发病机制。
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