TLR signalling augments macrophage bactericidal activity through mitochondrial ROS.
TLR signalling augments macrophage bactericidal activity through mitochondrial ROS.
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DOI：
10.1038/nature09973
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发表时间：
2011-04-28
期刊：
影响因子：
64.8
通讯作者：
Ghosh, Sankar
中科院分区：
文献类型：
--
作者：
West, A. Phillip;Brodsky, Igor E.;Rahner, Christoph;Woo, Dong Kyun;Erdjument-Bromage, Hediye;Tempst, Paul;Walsh, Matthew C.;Choi, Yongwon;Shadel, Gerald S.;Ghosh, Sankar
活性氧（ROS）是针对细胞内细菌的先天性免疫应答的基本组分，并且认为专职吞噬细胞主要通过吞噬体NADPH氧化酶（Phox）机制产生ROS。然而，最近的研究表明，线粒体活性氧（mROS）也有助于巨噬细胞杀菌活性，虽然连接先天性免疫信号转导线粒体的mROS生成的机制仍然不清楚。在这里，我们证明了Toll样受体（TLR1，TLR2和TLR4）的一个子集的参与导致线粒体向巨噬细胞吞噬体的募集，并增加mROS的产生。这种反应涉及TLR信号转导接头肿瘤坏死因子受体相关因子6（TRAF6）易位到线粒体，在线粒体中它参与Toll途径（ECSIT）中进化保守的信号转导中间体，一种参与线粒体呼吸链组装的蛋白质。与TRAF6的相互作用导致ECSIT泛素化和线粒体周边富集，导致线粒体和细胞ROS产生增加。ECSIT和TRAF6耗尽的巨噬细胞表现出TLR诱导的ROS水平降低，并且其杀死细胞内细菌的能力显著受损。此外，通过在线粒体中表达过氧化氢酶减少巨噬细胞mROS导致细菌杀伤缺陷，证实了mROS在杀菌活性中的作用。因此，这些结果揭示了一种将先天免疫信号传导与线粒体连接的新途径，暗示mROS是抗菌反应的重要组分，并进一步建立了线粒体作为先天免疫信号传导的枢纽。
Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria, and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase (Phox) machinery. However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to macrophage bactericidal activity, although the mechanisms linking innate immune signaling to mitochondria for mROS generation remain unclear. Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of the TLR signaling adapter tumor necrosis factor receptor-associated factor 6 (TRAF6) to mitochondria where it engages evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a protein implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT and TRAF6 depleted macrophages exhibit decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results therefore reveal a novel pathway linking innate immune signaling to mitochondria, implicate mROS as important components of antibacterial responses, and further establish mitochondria as hubs for innate immune signaling.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
3.8
作者：
Rousset, Sophie;Emre, Yalin;Cassard-Doulcier, Anne-Marie
通讯作者：
Cassard-Doulcier, Anne-Marie
影响因子：
64.5
作者：
Kang, Byoung Heon;Plescia, Janet;Altieri, Dario C.
通讯作者：
Altieri, Dario C.
影响因子：
6.6
作者：
Koopman, Werner J H;Nijtmans, Leo G J;Willems, Peter H G M
通讯作者：
Willems, Peter H G M