Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways
Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways
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DOI：
10.1016/j.neulet.2014.10.016
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发表时间：
2015-01-01
影响因子：
2.5
通讯作者：
Lee, Dong-Seok
中科院分区：
文献类型：
--
作者：
Park, Junghyung;Min, Ju-Sik;Lee, Dong-Seok
脑中小胶质细胞的活化有助于由许多神经毒性因子如促炎细胞因子和一氧化氮（NO）促进的神经退行性过程。活性氧（ROS）通过其作为促炎分子和促炎过程调节剂的作用积极影响小胶质细胞相关的神经退行性疾病。虽然参与小胶质细胞活化的ROS被认为主要由NADPH氧化酶（NOX）产生并参与免疫应答，但线粒体ROS也被认为是先天免疫系统中炎症应答的重要调节剂。然而，线粒体活性氧在小胶质细胞活化中的作用尚未完全阐明。在这项研究中，我们证明了通过用Mito-TEMPO处理来抑制线粒体ROS有效地抑制了线粒体和细胞内ROS的水平。Mito-TEMPO处理还显著防止BV-2和原代小胶质细胞中TNF-α、IL-1 β、IL-6、iNOS和考克斯-2的LPS诱导的增加。此外，LPS诱导的线粒体ROS生成的抑制不仅影响LPS刺激的MAPK活化，包括ERK、JNK和p38，而且还调节I κ B活化和NF-κ B核定位。这些结果表明，在LPS介导的活化的小胶质细胞中，线粒体构成ROS产生的主要来源。此外，LPS诱导的线粒体ROS的抑制通过阻止小胶质细胞中的MAPK和NF-κ B活化而在调节促炎介质的产生中起作用。我们的研究结果表明，一个潜在的策略，在炎症相关的退行性神经系统疾病的治疗发展涉及靶向小胶质细胞中的线粒体ROS的调节。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Activation of microglia cells in the brain contributes to neurodegenerative processes promoted by many neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO). Reactive oxygen species (ROS) actively affect microglia-associated neurodegenerative diseases through their role as pro-inflammatory molecules and modulators of pro-inflammatory processes. Although the ROS which involved in microglia activation are thought to be generated primarily by NADPH oxidase (NOX) and involved in the immune response, mitochondrial ROS have also been proposed as important regulators of the inflammatory response in the innate immune system. However, the role of mitochondrial ROS in microglial activation has yet to be fully elucidated. In this study, we demonstrate that inhibition of mitochondrial ROS by treatment with Mito-TEMPO effectively suppressed the level of mitochondrial and intracellular ROS. Mito-TEMPO treatment also significantly prevented LPS-induced increase in the TNF-alpha, IL-1 beta, IL-6, iNOS and Cox-2 in BV-2 and primary microglia cells. Furthermore, LPS-induced suppression of mitochondrial ROS generation not only affected LPS-stimulated activation of MAPKs, including ERK, JNK, and p38, but also regulated I kappa B activation and NF-kappa B nuclear localization. These results indicate that mitochondria constitute a major source of ROS generation in LPS-mediated activated microglia cells. Additionally, suppression of LPS-induced mitochondrial ROS plays a role in modulating the production of pro-inflammatory mediators by preventing MAPK and NF-kappa B activation in microglia cells. Our findings suggest that a potential strategy in the development of therapy for inflammation-associated degenerative neurological diseases involves targeting the regulation of mitochondrial ROS in microglial cells. (C) 2014 Elsevier Ireland Ltd. All rights reserved.