Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells
Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells
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DOI：
10.1111/jnc.12361
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发表时间：
2013-10-01
影响因子：
4.7
通讯作者：
Lee, Dong-Seok
中科院分区：
文献类型：
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作者：
Park, Junghyung;Choi, Hoonsung;Lee, Dong-Seok
脑内小胶质细胞的过度激活导致多种神经毒性因子的产生，包括促炎细胞因子和一氧化氮，从而促进了神经退变过程。近年来，越来越多的证据表明，线粒体动力学是细胞质量控制和功能的重要组成部分。然而，线粒体动力学在小胶质细胞激活中的作用在很大程度上仍不清楚。在这项研究中，我们确定了线粒体动力学是否与内毒素(LPS)刺激携带逆转录病毒(J2)的v-raf/v-myc诱导的小鼠小胶质细胞(BV-2)永生化过程中促炎介质的产生有关。在脂多糖刺激下，稳定表达DsRed2-mito的慢病毒BV-2细胞出现线粒体过度分裂。此外，动力蛋白相关蛋白1(Drp1)(线粒体分裂的关键调节因子)的线粒体定位增加，并伴随着DRp1中Ser637的去磷酸化。有趣的是，Mdivi-1和Drp1基因敲除抑制了内毒素诱导的线粒体分裂和活性氧物种(ROS)的产生，通过减少核因子-kappa-轻链-活化B细胞(NF-B)和丝裂原活化蛋白激酶(MAPK)信号，减少了促炎介质的产生。我们的结果首次证明了线粒体分裂通过激活NF-B和MAPK来调节激活的小胶质细胞线粒体ROS的产生，并影响促炎介质的表达。因此，我们认为线粒体动力学对于了解激活的小胶质细胞中促炎介质的表达可能是必不可少的。这可能代表着预防神经退行性疾病的一种新的治疗方法。
Over-activation of microglia cells in the brain contributes to neurodegenerative processes promoted by the production of various neurotoxic factors including pro-inflammatory cytokines and nitric oxide. Recently, accumulating evidence has suggested that mitochondrial dynamics are an important constituent of cellular quality control and function. However, the role of mitochondrial dynamics in microglial activation is still largely unknown. In this study, we determined whether mitochondrial dynamics are associated with the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated immortalization of murine microglial cells (BV-2) by a v-raf/v-myc carrying retrovirus (J2). Excessive mitochondrial fission was observed in lentivirus-transfected BV-2 cells stably expressing DsRed2-mito following LPS stimulation. Furthermore, mitochondrial localization of dynamin-related protein 1 (Drp1) (a key regulator of mitochondrial fission) was increased and accompanied by de-phosphorylation of Ser637 in Drp1. Interestingly, inhibition of LPS-induced mitochondrial fission and reactive oxygen species (ROS) generation by Mdivi-1 and Drp1 knock-down attenuated the production of pro-inflammatory mediators via reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) and mitogen-activated protein kinase (MAPK) signaling. Our results demonstrated for the first time that mitochondrial fission regulates mitochondrial ROS production in activated microglial cells and influences the expression of pro-inflammatory mediators through the activation of NF-B and MAPK. We therefore suggest that mitochondrial dynamics may be essential for understanding pro-inflammatory mediator expression in activated microglial cells. This could represent a new therapeutic approach for preventing neurodegenerative diseases.