Kasumba Dacquin M, Hajake Takara, Oh Seong-Wook, Kotenko Sergei V, Kato Hiroki, Fujita Takashi
Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507 Japan.
Laboratory of Molecular and Cellular Immunology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501 Japan; and.
J Immunol. 2017 Oct 1;199(7):2460-2474. doi: 10.4049/jimmunol.1700523. Epub 2017 Aug 28.
Nucleic acids carrying pathogen-associated molecular patterns trigger innate immune responses and are used to activate host immunity. Although synthetic nucleic acids have been used for that purpose, they have shown limitations for in vivo and clinical applications. To address this issue, we tested a naturally occurring dsRNA extracted from rice bran (rb-dsRNA) and characterized it as a potent ligand of TLR3 and MDA5. In this study, intranasal administration of rb-dsRNA induced production of type I IFNs by alveolar macrophages and protected mice from morbidity and mortality resulting from respiratory virus infection, such as influenza A virus. This protection was completely absent in mice lacking both TRIF and MDA5, indicating the essential role of TLR3- and MDA5-dependent pathways. Interestingly, IFNAR1-deficient mice retained residual antiviral protection, which was abolished by pharmacological inhibition of caspase 1, but not IL-1β signaling. In fact, rb-dsRNA activated caspase 1 via TRIF, resulting in the release of IL-1β and LDH. In addition to the direct antiviral activity, rb-dsRNA modulated the immune cell population in the lungs by repopulating virus-depleted alveolar macrophages. Our data demonstrate that rb-dsRNA orchestrates IFN-dependent and -independent direct antiviral protection and that it is a potent immune stimulator modulating antiviral immunity in the lungs. These findings open doors to a range of precise immune-modulating studies and therapeutic options.
携带病原体相关分子模式的核酸可触发先天免疫反应，并用于激活宿主免疫力。尽管合成核酸已用于此目的，但它们在体内和临床应用中显示出局限性。为了解决这个问题，我们测试了一种从米糠中提取的天然双链RNA（rb-dsRNA），并将其表征为TLR3和MDA5的有效配体。在本研究中，鼻内给予rb-dsRNA可诱导肺泡巨噬细胞产生I型干扰素，并保护小鼠免受呼吸道病毒感染（如甲型流感病毒）导致的发病和死亡。在同时缺乏TRIF和MDA5的小鼠中，这种保护作用完全消失，表明TLR3和MDA5依赖性途径的重要作用。有趣的是，IFNAR1缺陷小鼠保留了残余的抗病毒保护作用，这种作用可通过半胱天冬酶1的药理学抑制作用消除，但不能通过IL-1β信号传导消除。事实上，rb-dsRNA通过TRIF激活半胱天冬酶1，导致IL-1β和LDH的释放。除了直接抗病毒活性外，rb-dsRNA还通过重新填充病毒耗尽的肺泡巨噬细胞来调节肺中的免疫细胞群体。我们的数据表明，rb-dsRNA协调了IFN依赖性和非依赖性的直接抗病毒保护作用，并且它是一种有效的免疫刺激剂，可调节肺中的抗病毒免疫力。这些发现为一系列精确的免疫调节研究和治疗选择打开了大门。
