Influenza Virus-Induced Oxidized DNA Activates Inflammasomes
Influenza Virus-Induced Oxidized DNA Activates Inflammasomes
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DOI：
10.1016/j.isci.2020.101270
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发表时间：
2020-07-24
期刊：
影响因子：
5.8
通讯作者：
Ichinohe，Takeshi
中科院分区：
文献类型：
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作者：
Moriyama，Miyu;Nagai，Minami;Ichinohe，Takeshi
已经提出流感病毒M2和PB 1-F2蛋白通过改变细胞内离子平衡或线粒体活性氧（ROS）产生来激活巨噬细胞中的Nod样受体家族、含pyrin结构域3（NLRP 3）炎性体。然而，这些病毒蛋白触发NLRP 3炎性小体激活的确切机制仍不清楚。在这里，我们表明，流感病毒刺激氧化的DNA从巨噬细胞释放。氧化DNA释放需要M2蛋白的离子通道活性或PB 1-F2蛋白的线粒体定位。氧化的DNA增强流感病毒诱导的IL-1β分泌，而抗氧化剂Mito-TEMPO抑制线粒体ROS产生则降低病毒诱导的IL-1β分泌。此外，我们发现流感病毒以AIM 2依赖性方式刺激巨噬细胞分泌IL-1β。这些结果提供了流感病毒蛋白和NLRP 3炎性小体激活之间缺失的联系，并揭示了流感病毒诱导的氧化DNA在炎性小体激活中的重要性。
Influenza virus M2 and PB1-F2 proteins have been proposed to activate the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome in macrophages by altering intracellular ionic balance or mitochondrial reactive oxygen species (ROS) production. However, the precise mechanism by which these viral proteins trigger the NLRP3 inflammasome activation remains unclear. Here we show that influenza virus stimulates oxidized DNA release from macrophages. Ion channel activity of the M2 protein or mitochondrial localization of the PB1-F2 protein was required for oxidized DNA release. The oxidized DNA enhanced influenza virus-induced IL-1β secretion, whereas inhibition of mitochondrial ROS production by antioxidant Mito-TEMPO decreased the virus-induced IL-1β secretion. In addition, we show that influenza virus stimulates IL-1β secretion from macrophages in an AIM2-dependent manner. These results provide a missing link between influenza viral proteins and the NLRP3 inflammasome activation and reveal the importance of influenza virus-induced oxidized DNA in inflammasomes activation.