Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Johns Hopkins University School of Medicine, Pathology 517, 600 North Wolfe Street, Baltimore, MD 21287, USA.
J Neuroimmune Pharmacol. 2013 Sep;8(4):998-1009. doi: 10.1007/s11481-013-9471-7. Epub 2013 May 18.
Despite wide spread use of combination antiretroviral therapy (cART) in developed countries, approximately half of HIV-infected patients will develop impairments in cognitive function. Accumulating evidence suggests that neuronal dysfunction can be precipitated by HIV-infection of macrophages by mechanisms that involve alterations in innate and adaptive immune responses. HIV-infection of macrophages is known to increase the release of soluble neurotoxins. However, the composition of products released from infected macrophages is complex and not fully known. In this study we provide evidence that ATP and other immuno-/neuromodulatory nucleotides are exported from HIV-infected macrophages and modify neuronal structure. Supernatants collected from HIV-infected macrophages (HIV/MDM) contained large amounts of ATP, ADP, AMP and small amounts of adenosine, in addition to glutamate. Dilutions of these supernatants that were sub-threshold for glutamate receptor activation evoked rapid calcium flux in neurons that were completely inhibited by the enzymatic degradation of ATP, or by blockade of calcium permeable purinergic receptors. Applications of these highly diluted HIV/MDM onto neuronal cultures increased the amount of extracellular glutamate by mechanisms dependent on purinergic receptor activation, and downregulated spine density on neurons by mechanisms dependent on purinergic and glutamate receptor activation. We conclude from these data that ATP released from HIV-infected macrophages downregulates dendritic spine density on neurons by a mechanism that involves purinergic receptor mediated modulation of glutamatergic tone. These data suggest that neuronal function may be depressed in HIV infected individuals by mechanisms that involve macrophage release of ATP that triggers secondary effects on glutamate handling.
尽管在发达国家广泛使用联合抗逆转录病毒疗法（cART），但大约一半的 HIV 感染患者会出现认知功能障碍。越来越多的证据表明，通过涉及固有和适应性免疫反应改变的机制，HIV 感染巨噬细胞可引发神经元功能障碍。已知 HIV 感染巨噬细胞会增加可溶性神经毒素的释放。然而，从感染的巨噬细胞中释放的产物的组成很复杂，尚未完全了解。在这项研究中，我们提供了证据表明，ATP 和其他免疫/神经调节剂核苷酸从感染 HIV 的巨噬细胞中输出，并改变神经元结构。从 HIV 感染的巨噬细胞（HIV/MDM）收集的上清液中含有大量的 ATP、ADP、AMP 和少量的腺苷，以及谷氨酸。这些上清液的稀释液在谷氨酸受体激活的阈值以下，会在神经元中引起快速钙流，而钙流完全被 ATP 的酶促降解或钙通透性嘌呤能受体阻断所抑制。将这些高度稀释的 HIV/MDM 应用于神经元培养物中，通过依赖嘌呤能受体激活的机制增加细胞外谷氨酸的含量，并通过依赖嘌呤能和谷氨酸受体激活的机制下调神经元上的棘突密度。我们从这些数据中得出结论，HIV 感染的巨噬细胞释放的 ATP 通过嘌呤能受体介导的谷氨酸能张力调节来下调神经元上的树突棘密度。这些数据表明，神经元功能可能会受到 HIV 感染个体中涉及巨噬细胞释放 ATP 的机制的抑制，该机制会引发对谷氨酸处理的继发影响。
