Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation.
Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation.
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DOI：
10.1038/s41598-017-05232-0
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发表时间：
2017-07-10
影响因子：
4.6
通讯作者：
Ohno N
中科院分区：
文献类型：
--
作者：
Katoh M;Wu B;Nguyen HB;Thai TQ;Yamasaki R;Lu H;Rietsch AM;Zorlu MM;Shinozaki Y;Saitoh Y;Saitoh S;Sakoh T;Ikenaka K;Koizumi S;Ransohoff RM;Ohno N
小胶质细胞是中枢神经系统的驻留巨噬细胞，在包括髓鞘原发疾病在内的多种疾病中发挥着复杂的作用。虽然线粒体对神经系统中的细胞功能和生存至关重要，但线粒体动力学和相关信号在小胶质细胞中的变化和作用仍然知之甚少。在本研究中，通过结合免疫组织化学和三维超微结构分析，我们发现在髓鞘疾病模型中，反应性小胶质细胞的线粒体分裂/融合受到不同于单核细胞来源的巨噬细胞和正常白质分支小胶质细胞的调控。小鼠脑小胶质细胞体外实验表明，被广泛用于检测小胶质细胞反应的脂多糖刺激TLR4，可引起线粒体分裂蛋白、动力蛋白相关蛋白1(Drp1)的激活，并增加活性氧(ROS)的产生。ROS水平的升高激活了5‘-腺苷一磷酸活化蛋白激酶(AMPK)，并促进了线粒体沿微管轨迹的伸长。这些结果表明，炎症条件下反应性小胶质细胞线粒体分裂和融合的多态调控是由不同的信号介导的，并通过产生ROS来调节小胶质细胞的表型。
Microglia are the resident macrophages of the central nervous system and play complex roles in the milieu of diseases including the primary diseases of myelin. Although mitochondria are critical for cellular functions and survival in the nervous system, alterations in and the roles of mitochondrial dynamics and associated signaling in microglia are still poorly understood. In the present study, by combining immunohistochemistry and 3D ultrastructural analyses, we show that mitochondrial fission/fusion in reactive microglia is differentially regulated from that in monocyte-derived macrophages and the ramified microglia of normal white matter in myelin disease models. Mouse cerebral microglia in vitro demonstrated that stimulation of TLR4 with lipopolysaccharide, widely used to examine microglial reactions, caused the activation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1) and enhanced production of reactive oxygen species (ROS). The increase in the ROS level activated 5′ adenosine monophosphate-activated protein kinase (AMPK), and facilitated elongation of mitochondria along the microtubule tracks. These results suggest that the polymorphic regulation of mitochondrial fission and fusion in reactive microglia is mediated by distinct signaling under inflammatory conditions, and modulates microglial phenotypes through the production of ROS.
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