MicroRNA-15b Modulates Japanese Encephalitis Virus-Mediated Inflammation via Targeting RNF125
MicroRNA-15b Modulates Japanese Encephalitis Virus-Mediated Inflammation via Targeting RNF125
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MicroRNA-15b 通过靶向 RNF125 调节日本脑炎病毒介导的炎症。
DOI：
10.4049/jimmunol.1500370
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发表时间：
2015-09-01
影响因子：
4.4
通讯作者：
Cao, Shengbo
中科院分区：
文献类型：
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作者：
Zhu, Bibo;Ye, Jing;Cao, Shengbo
日本脑炎病毒（JEV）可靶向中枢神经系统并引起神经炎症，其特征在于严重的神经元损伤和伴随的小胶质细胞增生/星形胶质细胞增生。尽管microRNAs（miRNAs）已成为对炎症反应具有深远影响的主要调控网络，但它们如何调控JEV诱导的炎症尚不清楚。在这项研究中，我们发现miR-15 b参与调节JEV诱导的炎症反应。数据表明，miR-15 b在JEV感染神经胶质细胞和小鼠脑期间上调。miR-15 b在体外过表达可增强JEV诱导的炎症反应，而抑制miR-15 b则可降低JEV诱导的炎症反应。从机制上讲，RIG-I信号负调控因子环指蛋白125（RNF 125）被鉴定为miR-15 b在JEV感染背景下的直接靶点。此外，miR-15 b对RNF 125的抑制导致RIG-I水平升高，这反过来导致促炎细胞因子和I型IFN的更高产生。通过antagomir-15 b体内敲除病毒诱导的miR-15 b可以恢复RNF 125的表达，减少炎症细胞因子的产生，减弱胶质细胞活化和神经元损伤，减少大脑中的病毒负荷，并提高小鼠模型的存活率。综上所述，我们的结果表明，miR-15 b通过负调节RNF 125表达来调节JEV感染期间的炎症反应。因此，miR-15 b靶向可能构成控制病毒诱导的神经炎症的有趣且有前途的方法。
Japanese encephalitis virus (JEV) can target CNS and cause neuroinflammation that is characterized by profound neuronal damage and concomitant microgliosis/astrogliosis. Although microRNAs (miRNAs) have emerged as a major regulatory network with profound effects on inflammatory response, it is less clear how they regulate JEV-induced inflammation. In this study, we found that miR-15b is involved in modulating the JEV-induced inflammatory response. The data demonstrate that miR-15b is upregulated during JEV infection of glial cells and mouse brains. In vitro overexpression of miR-15b enhances the JEV-induced inflammatory response, whereas inhibition of miR-15b decreases it. Mechanistically, ring finger protein 125 (RNF125), a negative regulator of RIG-I signaling, is identified as a direct target of miR-15b in the context of JEV infection. Furthermore, inhibition of RNF125 by miR-15b results in an elevation in RIG-I levels, which, in turn, leads to a higher production of proinflammatory cytokines and type I IFN. In vivo knockdown of virus-induced miR-15b by antagomir-15b restores the expression of RNF125, reduces the production of inflammatory cytokines, attenuates glial activation and neuronal damage, decreases viral burden in the brain, and improves survival in the mouse model. Taken together, our results indicate that miR-15b modulates the inflammatory response during JEV infection by negative regulation of RNF125 expression. Therefore, miR-15b targeting may constitute an interesting and promising approach to control viral-induced neuroinflammation.