Critical Role of Beclin1 in HIV Tat and Morphine-Induced Inflammation and Calcium Release in Glial Cells from Autophagy Deficient Mouse.
Critical Role of Beclin1 in HIV Tat and Morphine-Induced Inflammation and Calcium Release in Glial Cells from Autophagy Deficient Mouse.
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DOI：
10.1007/s11481-018-9788-3
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
El-Hage N
中科院分区：
文献类型：
--
作者：
Lapierre J;Rodriguez M;Ojha CR;El-Hage N
我们之前的研究表明，自噬是人类免疫缺陷病毒（HIV）复制和吗啡诱导的人类星形胶质细胞和小胶质细胞联合神经炎症的重要组成部分。在这里，我们进一步研究了部分缺乏必要的自噬基因Atg6 （Beclin1）的小鼠胶质细胞暴露于HIV Tat和吗啡的自噬后果。已知它会引起炎症反应，增加钙释放，并可能与自噬途径蛋白相互作用。与对照组（C57BL/6J）小鼠相比，Tat暴露后，自噬缺陷（Becn1+/−）胶质细胞的促炎细胞因子IL-6和趋化因子RANTES和MCP-1水平显著且持续降低，这表明Tat和Beclin1的炎症作用之间存在关联。此外，经Tat和吗啡处理的C57BL/6J和Becn1+/−胶质细胞之间RANTES和MCP-1分泌的差异也表明Beclin1在吗啡诱导的增强中起作用。免疫印迹自噬成熟分析表明，Beclin1可能是Tat必需的，在较小程度上吗啡诱导的通路阻滞，如C57BL/6J胶质细胞中接头蛋白p62/SQSTM1的积累所证明的那样。在Beclin1+/−或C57BL/6J胶质细胞中，Tat单独或联合吗啡诱导的钙释放在Beclin1+/−胶质细胞中显著减少，而在Becn1+/−或C57BL/6J衍生的胶质细胞中，Tat与吗啡对活性氧或活性氮产生的相互作用很小。总的来说，这些数据确定了Beclin1在Tat和吗啡介导的炎症反应和神经胶质细胞钙释放中的作用，并支持自噬介导Tat单独和联合吗啡诱导的神经病理的观点。
We previously showed that autophagy is an important component in human immunodeficiency virus (HIV) replication and in the combined morphine-induced neuroinflammation in human astrocytes and microglia. Here we further studied the consequences of autophagy using glial cells of mice partially lacking the essential autophagy gene Atg6 (Beclin1) exposed to HIV Tat and morphine. Tat is known to cause an inflammatory response, increase calcium release, and possibly interact with autophagy pathway proteins. Following Tat exposure, autophagy-deficient (Becn1+/−) glial cells had significantly and consistently reduced levels in the pro-inflammatory cytokine IL-6 and the chemokines RANTES and MCP-1 when compared to Tat-treated cells from control (C57BL/6J) mice, suggesting an association between the inflammatory effects of Tat and Beclin1. Further, differences in RANTES and MCP-1 secretion between C57BL/6J and Becn1+/− glia treated with Tat and morphine also suggest a role of Beclin1 in the morphine-induced enhancement. Analysis of autophagy maturation by immunoblot suggests that Beclin1 may be necessary for Tat, and to a lesser extent morphine-induced arrest of the pathway as demonstrated by accumulation of the adaptor protein p62/SQSTM1 in C57BL/6J glia. Calcium release induced by Tat alone or in combination with morphine in C57BL/6J glia was significantly reduced in Beclin1+/− glia while minimal interactive effect of Tat with morphine in the production of reactive oxygen or nitrogen species was detected in glia derived from Becn1+/− or C57BL/6J. Overall, the data establish a role of Beclin1 in Tat and morphine-mediated inflammatory responses and calcium release in glial cells and support the notion that autophagy mediates Tat alone and combined morphine-induced neuropathology.
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