Dopamine and its receptors play a role in the modulation of CCR5 expression in innate immune cells following exposure to Methamphetamine: Implications to HIV infection.
Dopamine and its receptors play a role in the modulation of CCR5 expression in innate immune cells following exposure to Methamphetamine: Implications to HIV infection.
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DOI：
10.1371/journal.pone.0199861
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Marcondes MCG
中科院分区：
文献类型：
--
作者：
Basova L;Najera JA;Bortell N;Wang D;Moya R;Lindsey A;Semenova S;Ellis RJ;Marcondes MCG
人类免疫缺陷病毒（HIV）感染中枢神经系统（CNS）中的细胞，其中可以杀死病毒的抗逆转录病毒药物和抗体的获得可能具有挑战性。由于艾滋病毒早期进入大脑，受感染者会出现不同程度的炎症和神经功能缺损，滥用药物会加重这些症状。在HIV的非人灵长类动物模型中，我们先前已经表明，滥用药物如甲基苯丙胺（Meth）会增加脑病毒载量，这与更高数量的CCR5表达骨髓细胞相关。CCR5是一种趋化因子受体，可能参与增加炎症，但它也是病毒进入靶细胞的辅助受体。表达CCR5的骨髓细胞是CNS中HIV的主要靶点。因此，识别影响大脑中CCR5表达的因素和机制至关重要，因为CCR5水平的变化可能会影响大脑中的感染。使用一个良好的特点，在体外系统，与THP 1人巨噬细胞系，我们已经研究了假设CCR5的表达是急性影响的甲基，并检查这种效果可能发生的途径。我们发现，Meth通过调节CCR 5启动子中具有结合位点的转录因子的丰度和核转位发挥直接作用。然而，我们发现，在表观遗传水平上修饰CCR5基因启动子的主要因素是多巴胺（DA），这是一种主要在富含多巴胺能神经元的大脑区域产生的神经递质。在THP 1细胞中，DA对天然免疫CCR5转录的影响是由DA受体（DRD）介导的，主要是DRD 4。我们还确定了DRD1在抑制骨髓细胞系统中CCR5表达中的作用，这对治疗有潜在的意义。DA对先天免疫CCR5表达的影响也可在急性时间点在细胞表面检测到，使用低剂量。此外，HIV达特通过增强CCR 5的表面表达发挥作用，尽管其对转录的影响很差。总体而言，我们的数据表明，在HIV肽（如达特）存在的情况下，髓样细胞暴露于甲基，可能通过DA依赖性和非依赖性机制的组合，通过调节CCR 5表达来影响HIV靶标的数量。其他增加DA的药物可能会影响类似的机制。这些表观遗传和翻译机制在增强艾滋病毒感染的大脑和其他地方的影响被证明。
The Human Immunodeficiency Virus (HIV) infects cells in the Central Nervous System (CNS), where the access of antiretrovirals and antibodies that can kill the virus may be challenging. As a result of the early HIV entry in the brain, infected individuals develop inflammation and neurological deficits at various levels, which are aggravated by drugs of abuse. In the non-human primate model of HIV, we have previously shown that drugs of abuse such as Methamphetamine (Meth) increase brain viral load in correlation with a higher number of CCR5-expressing myeloid cells. CCR5 is a chemokine receptor that may be involved in increasing inflammation, but also, it is a co-receptor for viral entry into target cells. CCR5-expressing myeloid cells are the main targets of HIV in the CNS. Thus, the identification of factors and mechanisms that impact the expression of CCR5 in the brain is critical, as changes in CCR5 levels may affect the infection in the brain. Using a well-characterized in vitro system, with the THP1 human macrophage cell line, we have investigated the hypothesis that the expression of CCR5 is acutely affected by Meth, and examined pathways by which this effect could happen. We found that Meth plays a direct role by regulating the abundance and nuclear translocation of transcription factors with binding sites in the CCR5 promoter. However, we found that the main factor that modifies the CCR5 gene promoter at the epigenetic level towards transcription is Dopamine (DA), a neurotransmitter that is produced primarily in brain regions that are rich in dopaminergic neurons. In THP1 cells, the effect of DA on innate immune CCR5 transcription was mediated by DA receptors (DRDs), mainly DRD4. We also identified a role for DRD1 in suppressing CCR5 expression in this myeloid cell system, with potential implications for therapy. The effect of DA on innate immune CCR5 expression was also detectable on the cell surface during acute time-points, using low doses. In addition, HIV Tat acted by enhancing the surface expression of CCR5, in spite of its poor effect on transcription. Overall, our data suggests that the exposure of myeloid cells to Meth in the context of presence of HIV peptides such as Tat, may affect the number of HIV targets by modulating CCR5 expression, through a combination of DA-dependent and–independent mechanisms. Other drugs that increase DA may affect similar mechanisms. The implications of these epigenetic and translational mechanisms in enhancing HIV infection in the brain and elsewhere are demonstrated.
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