MiR-142a-3p and miR-155-5p reduce methamphetamine-induced inflammation: Role of the target protein Peli1
MiR-142a-3p and miR-155-5p reduce methamphetamine-induced inflammation: Role of the target protein Peli1
复制标题
miR-142a-3p 和 miR-155-5p 减少甲基苯丙胺诱导的炎症：靶蛋白 Peli1 的作用
DOI：
10.1016/j.taap.2019.03.019
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发表时间：
2019
影响因子：
3.8
通讯作者：
Tang Jinrong
中科院分区：
文献类型：
--
作者：
Yu Guoqin;Song Yang;Xie Cuiwei;Tao Liyuan;Wan Fen;Jiang Lei;Wang Jun;Tang Jinrong
甲基苯丙胺（methamphetamine，METH）是一种高度成瘾性的兴奋剂，暴露于METH可引起一系列神经炎症反应。Peli 1是一种新的和重要的E3泛素蛋白连接酶，有助于神经炎症;因此，靶向Peli 1可能为神经炎症提供有前途的治疗策略。除了经典的MyD 88依赖性或MyD 88非依赖性途径外，miRNA也可能参与Peli 1的调节。在本研究中，选择了两种新的miRNAs，miR-142 a-3 p和miR-155- 5 p，它们被预测为靶向Peli 1，并通过调节Peli 1表达来鉴定它们在METH诱导的神经炎症中的独特作用。我们的研究结果表明，miR-142 a-3 p在MET诱导的神经炎症中显著降低，并且与BV 2细胞和小鼠脑中的Peli 1表达呈负相关。MiR-155- 5 p在体外被METH显著降低，但在体内增加。进行荧光素酶报告基因测定以揭示miR-142 a-3 p和miR-155- 5 p特异性结合Peli 1，这种作用被Peli 1结合位点突变完全消除。反过来，miR-142 a-3 p和miR-155- 5 p的过表达可以直接抑制Peli 1的表达，并可以部分通过激活p38 MAPK和NF-κB炎症通路来保护METH治疗的炎症效应。总之，本研究揭示了一条新的信号通路，即miR-142 a-3 p/miR-155- 5 p/Peli 1轴在METH介导的神经炎症中的作用，该通路可能是METH介导的神经毒性的潜在治疗靶点。
Methamphetamine (METH) is a highly addictive stimulant and METH exposure can induce a series of neuroinflammatory effects. Peli1 is a novel and important E3 ubiquitin-protein ligase contributing to neuroinflammation; targeting Peli1 may thus provide promising therapeutic strategies for neuroinflammation. In addition to the classic MyD88-dependent or MyD88-independent pathways, miRNAs may also be involved in Peli1 modulation. In the present study, two novel miRNAs, miR-142a-3p and miR-155-5p, that were predicted to target Peli1 using bioinformatics were chosen, and their unique roles in METH-induced neuroinflammation via regulating Peli1 expression were identified. Our results showed that miR-142a-3p was significantly reduced in METH-induced neuroinflammation and was negatively associated with Peli1 expression both in BV2 cells and in the brain of mouse. MiR-155-5p was significantly reduced by METH in vitro but increased in vivo. A luciferase reporter assay was performed to reveal that miR-142a-3p and miR-155-5p bound specifically to Peli1, an effect that was completely abolished by the Peli1 binding site mutation. Reciprocally, the overexpression of miR-142a-3p and miR-155-5p could directly suppress Peli1 expression and could protect against the inflammatory effects of METH treatment partially through activating p38 MAPK and NF-κB inflammatory pathways. In conclusion, the present study reveals a novel signaling pathway, the miR-142a-3p/miR-155-5p/Peli1 axis in METH-mediated neuroinflammation, and this pathway could be a potential therapeutic target for METH-mediated neurotoxicity.