Methamphetamine potentiates HIV-1 gp120-mediated autophagy via Beclin-1 and Atg5/7 as a pro-survival response in astrocytes.
Methamphetamine potentiates HIV-1 gp120-mediated autophagy via Beclin-1 and Atg5/7 as a pro-survival response in astrocytes.
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DOI：
10.1038/cddis.2016.317
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发表时间：
2016-10-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
甲基苯丙胺（METH）是一种常用的受控物质，已知会加剧HIV感染者的神经病理功能障碍。神经病理学表现由中枢神经系统（CNS）中的细胞死亡或功能障碍引起，其中自噬预期具有重要作用。自噬通常被认为在剥夺/压力期间具有保护作用。然而，过度的自噬可能是破坏性的，导致自噬性细胞死亡。本研究旨在研究METH和HIV-1 gp 120是否相互作用以诱导SVGA星形胶质细胞中的自噬，以及自噬是否是副现象或在METH和gp 120诱导的细胞毒性中起作用。我们发现METH和gp 120 IIIb以剂量和时间依赖性的方式引起星形胶质细胞中LC 3 II水平的增加，并且当细胞用METH和gp 120 IIIb组合处理时，LC 3 II的水平进一步增加。接下来，我们试图探索METH和gp 120诱导自噬反应的机制。我们发现METH通过阿片样物质和代谢型谷氨酸受体5（mGluR 5）受体诱导自噬。除此之外，信号蛋白Akt、mTOR、Beclin-1、Atg 5和Atg 7也参与METH和gp 120介导的自噬。此外，METH和gp 120 IIIb的长期治疗导致细胞死亡，这是由自噬抑制加剧。这表明，自噬作为一种保护性反应，对抗METH和gp 120引起的细胞凋亡。这项研究是新颖的和临床相关的，因为艾滋病毒感染人群中的甲基苯丙胺滥用是非常普遍的，并已知会导致神经艾滋病的恶化。
Methamphetamine (METH), a commonly used controlled substance, is known to exacerbate neuropathological dysfunction in HIV-infected individuals. The neuropathological manifestation results from cell death or dysfunction in the central nervous system (CNS) wherein autophagy is expected to have an important role. Autophagy is generally considered protective during deprivation/stress. However, excessive autophagy can be destructive, leading to autophagic cell death. This study was designed to investigate if METH and HIV-1 gp120 interact to induce autophagy in SVGA astrocytes, and whether autophagy is epiphenomenal or it has a role in METH- and gp120-induced cytotoxicity. We found that METH and gp120 IIIb caused an increase in LC3II level in astrocytes in a dose- and time-dependent manner, and the level of LC3II was further increased when the cells were treated with METH and gp120 IIIb in combination. Next, we sought to explore the mechanism by which METH and gp120 induce the autophagic response. We found that METH induces autophagy via opioid and metabotropic glutamate receptor type 5 (mGluR5) receptors. Other than that, signaling proteins Akt, mammalian target of rapamycin (mTOR), Beclin-1, Atg5 and Atg7 were involved in METH and gp120-mediated autophagy. In addition, long-term treatment of METH and gp120 IIIb resulted in cell death, which was exacerbated by inhibition of autophagy. This suggests that autophagy functions as a protective response against apoptosis caused by METH and gp120. This study is novel and clinically relevant because METH abuse among HIV-infected populations is highly prevalent and is known to cause exacerbated neuroAIDS.
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