Zhang Hongbo, Luo Jiadi, Alcorn John F, Chen Kong, Fan Songqing, Pilewski Joseph, Liu Aizhong, Chen Wei, Kolls Jay K, Wang Jieru
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224.
Department of Pathology, Second Affiliated Xiangya Hospital, Central South University, Changsha 410078, China.
J Immunol. 2017 Jun 1;198(11):4383-4393. doi: 10.4049/jimmunol.1600714. Epub 2017 Apr 19.
The absent in melanoma 2 (AIM2) inflammasome plays an important role in many viral and bacterial infections, but very little is known about its role in RNA virus infection, including influenza A virus (IAV). In this study, we have designed in vivo and in vitro studies to determine the role of AIM2 in infections with lethal doses of IAVs A/PR8/34 and A/California/07/09. In wild-type mice, IAV infection enhanced AIM2 expression, induced dsDNA release, and stimulated caspase-1 activation and release of cleaved IL-1β in the lung, which was significantly reduced in AIM2-deficient mice. Interestingly, AIM2 deficiency did not affect the transcription of caspase-1 and IL-1β. In addition, AIM2-deficient mice exhibited attenuated lung injury and significantly improved survival against IAV challenges, but did not alter viral burden in the lung. However, AIM2 deficiency did not seem to affect adaptive immune response against IAV infections. Furthermore, experiments with AIM2-specific small interfering RNA-treated and AIM2-deficient human and mouse lung alveolar macrophages and type II cells indicated a macrophage-specific function of AIM2 in regulation of IAV-stimulated proinflammatory response. Collectively, our results demonstrate that influenza infection activates the AIM2 inflammasome, which plays a critical role in IAV-induced lung injury and mortality. AIM2 might serve as a therapeutic target for combating influenza-associated morbidity and mortality without compromising the host antiviral responses.
黑色素瘤缺乏因子2（AIM2）炎性小体在许多病毒和细菌感染中发挥重要作用，但对于其在包括甲型流感病毒（IAV）在内的RNA病毒感染中的作用却知之甚少。在本研究中，我们设计了体内和体外实验，以确定AIM2在致死剂量的IAV A/PR8/34和A/California/07/09感染中的作用。在野生型小鼠中，IAV感染增强了AIM2的表达，诱导双链DNA释放，并刺激了肺中caspase-1的活化以及裂解的IL-1β的释放，而在AIM2缺陷小鼠中这些作用显著降低。有趣的是，AIM2缺陷并不影响caspase-1和IL-1β的转录。此外，AIM2缺陷小鼠表现出减轻的肺损伤，并在IAV攻击后生存率显著提高，但并未改变肺中的病毒载量。然而，AIM2缺陷似乎并不影响针对IAV感染的适应性免疫反应。此外，用AIM2特异性小干扰RNA处理的以及AIM2缺陷的人和小鼠肺泡巨噬细胞及II型细胞的实验表明，AIM2在调节IAV刺激的促炎反应中具有巨噬细胞特异性功能。总体而言，我们的结果表明流感感染激活了AIM2炎性小体，其在IAV诱导的肺损伤和死亡率中起关键作用。AIM2可能作为一个治疗靶点，用于对抗流感相关的发病率和死亡率，而不损害宿主的抗病毒反应。
