Methamphetamine Enhances HIV-Induced Aberrant Proliferation of Neural Progenitor Cells via the FOXO3-Mediated Mechanism.
Methamphetamine Enhances HIV-Induced Aberrant Proliferation of Neural Progenitor Cells via the FOXO3-Mediated Mechanism.
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DOI：
10.1007/s12035-021-02407-9
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发表时间：
2021-11
影响因子：
5.1
通讯作者：
Toborek M
中科院分区：
文献类型：
--
作者：
Park M;Baker W;Cambow D;Gogerty D;Leda AR;Herlihy B;Pavlenko D;Van Den Nieuwenhuizen S;Toborek M
维持完整的神经祖细胞（NPC）池对于生成新的、功能活跃的神经元至关重要。甲基苯丙胺 (METH) 会加剧 HIV 引起的成人神经发生缺陷；然而，人们对这种影响的潜在机制仍然知之甚少。在本研究中，我们提供的证据表明，长期暴露于冰毒和 EcoHIV 脑部感染会导致小鼠脑室下区 (SVZ) NPC 增殖增强。这种效应是持久的，因为在没有额外治疗的情况下，它在从暴露的小鼠中分离的 NPC 中保留了数代。对 METH 加 HIV 的反应增加的增殖与细胞周期蛋白 B1 和细胞周期蛋白 D 的失调相关。转录组学研究表明，对 METH 加 EcoHIV 反应的前 30 个差异表达基因中有 27 个是叉头盒 O 转录因子 (FOXO) 的靶标，主要是 FOXO3。使用接触 METH 并感染 HIV 的人类 NPC 进行的其他离体研究和体外实验显示，CXCL12-CXCR4 轴上调，导致下游 pAkt 和 pErk 激活，这些途径可以磷酸化 FOXO3 并迫使其从细胞核输出到细胞质。事实上，FOXO3 的核排出在暴露于 METH 并感染 EcoHIV 的小鼠以及人类 NPC 的细胞培养物中均得到证实。这些结果提供了新的信息，即接触 METH 并结合 HIV 感染可诱导 SVZ 衍生的 NPC 异常增殖，并确定 CXCL12-CXCR4-Akt-1 介导的 FOXO3 磷酸化是造成这种效应的机制。在线版本包含可在 10.1007/s12035-021-02407-9 获取的补充材料。
Maintaining an intact pool of neural progenitor cells (NPCs) is crucial for generating new and functionally active neurons. Methamphetamine (METH) can exacerbate the HIV-induced deficit of adult neurogenesis; however, potential mechanisms of this influence are still poorly understood. In the present study, we present evidence that chronic exposure to METH combined with brain infection by EcoHIV results in enhanced proliferation of NPCs in the subventricular zone (SVZ) in mice. This effect was long-lasting as it was preserved ex vivo in NPCs isolated from the exposed mice over several passages in the absence of additional treatments. Increased proliferation in response to METH plus HIV was associated with dysregulation of cyclin B1 and cyclin D. Transcriptomic studies indicated that 27 out of the top 30 differentially expressed genes in response to METH plus EcoHIV were targets of the forkhead box O transcriptional factor (FOXO) and primarily FOXO3. Additional ex vivo studies and in vitro experiments using human NPCs exposed to METH and infected with HIV revealed upregulation of the CXCL12-CXCR4 axis, leading to activation of downstream pAkt and pErk, the pathways that can phosphorylate FOXO3 and force its exports from the nuclei into the cytoplasm. Indeed, nuclear expulsion of FOXO3 was demonstrated both in mice exposed to METH and infected with EcoHIV and in cell cultures of human NPCs. These results provide novel information that exposure to METH combined with HIV infection can induce aberrant proliferation of SVZ-derived NPCs and identifies CXCL12-CXCR4-Akt-1-mediated phosphorylation of FOXO3 as the mechanism responsible for this effect. The online version contains supplementary material available at 10.1007/s12035-021-02407-9.
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影响因子：
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