El-Hage Nazira, Wu Guanghan, Wang Juan, Ambati Jayakrishna, Knapp Pamela E, Reed Janelle L, Bruce-Keller Annadora J, Hauser Kurt F
Department of Anatomy and Neurobiology, University of Kentucky Chandler Medical Center, Lexington, Kentucky 40536-0298, USA.
Glia. 2006 Jan 15;53(2):132-46. doi: 10.1002/glia.20262.
Opiates exacerbate human immunodeficiency virus type 1 (HIV-1) Tat(1-72)-induced release of key proinflammatory cytokines by astrocytes, which may accelerate HIV neuropathogenesis in opiate abusers. The release of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), in particular, is potentiated by opiate-HIV Tat interactions in vitro. Although MCP-1 draws monocytes/macrophages to sites of CNS infection, and activated monocytes/microglia release factors that can damage bystander neurons, the role of MCP-1 in neuro-acquired immunodeficiency syndrome (neuroAIDS) progression in opiate abusers, or nonabusers, is uncertain. Using a chemotaxis assay, N9 microglial cell migration was found to be significantly greater in conditioned medium from mouse striatal astrocytes exposed to morphine and/or Tat(1-72) than in vehicle-, mu-opioid receptor (MOR) antagonist-, or inactive, mutant Tat(delta31-61)-treated controls. Conditioned medium from astrocytes treated with morphine and Tat caused the greatest increase in motility. The response was attenuated using conditioned medium immunoneutralized with MCP-1 antibodies, or medium from MCP-1(-/-) astrocytes. In the presence of morphine (time-release, subcutaneous implant), intrastriatal Tat increased the proportion of neural cells that were astroglia and F4/80+ macrophages at 7 days post-injection. This was not seen after treatment with Tat alone, or with morphine plus inactive Tat(delta31-61) or naltrexone. Glia displayed increased MOR and MCP-1 immunoreactivity after morphine and/or Tat exposure. The findings indicate that MCP-1 underlies most of the response of microglia, suggesting that one way in which opiates exacerbate neuroAIDS is by increasing astroglial-derived proinflammatory chemokines at focal sites of CNS infection and promoting macrophage entry and local microglial activation. Importantly, increased glial expression of MOR can trigger an opiate-driven amplification/positive feedback of MCP-1 production and inflammation.
阿片类药物会加剧1型人类免疫缺陷病毒（HIV-1）Tat(1-72)诱导的星形胶质细胞释放关键促炎细胞因子，这可能会加速阿片类药物滥用者的HIV神经病变进程。特别是，单核细胞趋化蛋白-1（MCP-1，也称为CCL2）的释放在体外会因阿片类药物与HIV Tat的相互作用而增强。虽然MCP-1会将单核细胞/巨噬细胞吸引到中枢神经系统感染部位，并且活化的单核细胞/小胶质细胞会释放可损害周围神经元的因子，但MCP-1在阿片类药物滥用者或非滥用者的神经获得性免疫缺陷综合征（神经艾滋病）进展中的作用尚不确定。通过趋化性测定发现，与载体、μ-阿片受体（MOR）拮抗剂或无活性的突变体Tat(delta31-61)处理的对照组相比，暴露于吗啡和/或Tat(1-72)的小鼠纹状体星形胶质细胞的条件培养基中，N9小胶质细胞的迁移明显更大。用吗啡和Tat处理的星形胶质细胞的条件培养基导致运动性增加最大。使用用MCP-1抗体免疫中和的条件培养基或来自MCP-1(-/-)星形胶质细胞的培养基，该反应减弱。在存在吗啡（缓释，皮下植入）的情况下，纹状体内注射Tat会在注射后7天增加神经胶质细胞和F4/80+巨噬细胞的神经细胞比例。单独用Tat或用吗啡加无活性的Tat(delta31-61)或纳曲酮处理后未观察到此现象。在暴露于吗啡和/或Tat后，神经胶质细胞显示出MOR和MCP-1免疫反应性增加。这些发现表明MCP-1是小胶质细胞大部分反应的基础，这表明阿片类药物加剧神经艾滋病的一种方式是通过增加中枢神经系统感染局部部位星形胶质细胞衍生的促炎趋化因子，并促进巨噬细胞进入和局部小胶质细胞活化。重要的是，神经胶质细胞中MOR表达的增加可触发阿片类药物驱动的MCP-1产生和炎症的放大/正反馈。
