Toll-Like Receptor 4 Mediates Methamphetamine-Induced Neuroinflammation through Caspase-11 Signaling Pathway in Astrocytes.
Toll-Like Receptor 4 Mediates Methamphetamine-Induced Neuroinflammation through Caspase-11 Signaling Pathway in Astrocytes.
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Toll 样受体 4 通过星形胶质细胞中的 Caspase-11 信号通路介导甲基苯丙胺诱导的神经炎症。
DOI：
10.3389/fnmol.2017.00409
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发表时间：
2017
影响因子：
4.8
通讯作者：
Xie WB
中科院分区：
文献类型：
--
作者：
Du SH;Qiao DF;Chen CX;Chen S;Liu C;Lin Z;Wang H;Xie WB
甲基苯丙胺（METH）是一种苯丙胺类兴奋剂药物，在世界范围内日益被滥用。先前的研究表明，METH毒性是全身性的，特别是靶向中枢神经系统（CNS）中的多巴胺能神经元。然而，神经炎症在METH神经毒性中的作用仍不清楚。我们假设Toll样受体4（TLR 4）和Caspase-11参与了MET诱导的星形胶质细胞相关的神经炎症。我们通过Western blot和免疫荧光双标记检测原代培养的C57 BL/6小鼠星形胶质细胞和METH暴露小鼠中脑和纹状体中TLR 4和Caspase-11蛋白表达的变化来验证我们的假设。我们还确定了阻断Caspase-11的表达与wedelolactone（Caspase-11的特异性抑制剂）或siRNA的影响，在星形胶质细胞的甲基诱导的神经炎症。此外，我们确定了用TAK-242（TLR 4的特异性抑制剂）或siRNA阻断TLR 4表达对星形胶质细胞中MET诱导的神经炎症的影响。METH暴露增加Caspase-11和TLR 4的表达在体外和体内，在体外的效果是剂量依赖性的。用wedelolactone或siRNAs抑制Caspase-11表达降低了炎性体NLRP 3和促炎细胞因子的表达。阻断TLR 4表达可抑制MET诱导的NF-κB和Caspase-11的活化，提示TLR 4-Caspase-11通路参与了MET诱导的神经炎症反应。这些结果表明，Caspase-11和TLR 4在MET诱导的神经炎症中起重要作用，并且可能是治疗MET引起的神经毒性的潜在基因靶点。
Methamphetamine (METH) is an amphetamine-typed stimulant drug that is increasingly being abused worldwide. Previous studies have shown that METH toxicity is systemic, especially targeting dopaminergic neurons in the central nervous system (CNS). However, the role of neuroinflammation in METH neurotoxicity remains unclear. We hypothesized that Toll-like receptor 4 (TLR4) and Caspase-11 are involved in METH-induced astrocyte-related neuroinflammation. We tested our hypothesis by examining the changes of TLR4 and Caspase-11 protein expression in primary cultured C57BL/6 mouse astrocytes and in the midbrain and striatum of mice exposed to METH with western blot and double immunofluorescence labeling. We also determined the effects of blocking Caspase-11 expression with wedelolactone (a specific inhibitor of Caspase-11) or siRNA on METH-induced neuroinflammation in astrocytes. Furthermore, we determined the effects of blocking TLR4 expression with TAK-242 (a specific inhibitor of TLR4) or siRNA on METH-induced neuroinflammation in astrocytes. METH exposure increased Caspase-11 and TLR4 expression both in vitro and in vivo, with the effects in vitro being dose-dependent. Inhibition of Caspase-11 expression with either wedelolactone or siRNAs reduced the expression of inflammasome NLRP3 and pro-inflammatory cytokines. In addition, blocking TLR4 expression inhibited METH-induced activation of NF-κB and Caspase-11 in vitro and in vivo, suggesting that TLR4-Caspase-11 pathway is involved in METH-induced neuroinflammation. These results indicate that Caspase-11 and TLR4 play an important role in METH-induced neuroinflammation and may be potential gene targets for therapeutics in METH-caused neurotoxicity.
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影响因子：
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作者：
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DOI：
10.1002/hep.29078
发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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