Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada.
Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada.
Viruses. 2018 Aug 9;10(8):419. doi: 10.3390/v10080419.
Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome plays a pivotal role in modulating lung inflammation in response to the influenza A virus infection. We previously showed that the swine influenza virus (SIV) infection induced NLRP3 inflammasome-mediated IL-1β production in primary porcine alveolar macrophages (PAMs), and we were interested in examining the upstream signaling events that are involved in this process. Here, we report that the SIV-infection led to dynamin-related protein 1 (DRP1) phosphorylation at serine 579 and mitochondrial fission in PAMs. IL-1β production was dependent on the reactive oxygen species (ROS) production, and DRP1 phosphorylation resulted in the upregulation of the NLRP3 inflammasome. Furthermore, the requirement of the kinase activity of receptor-interacting protein kinase 1 (RIPK1) for the IL-1β production and RIPK1-DRP1 association suggested that RIPK1 is an upstream kinase for DRP1 phosphorylation. Our results reveal a critical role of the RIPK1/DRP1 signaling axis, whose activation leads to mitochondrial fission and ROS release, in modulating porcine NLRP3 inflammasome-mediated IL-1β production in SIV-infected PAMs.
核苷酸结合域和富含亮氨酸重复蛋白 3（NLRP3）炎症小体在调节流感病毒感染引起的肺部炎症中起着关键作用。我们之前表明，猪流感病毒（SIV）感染诱导原代猪肺泡巨噬细胞（PAMs）中 NLRP3 炎症小体介导的白细胞介素-1β（IL-1β）产生，我们有兴趣研究参与这一过程的上游信号事件。在这里，我们报告 SIV 感染导致 PAMs 中动力相关蛋白 1（DRP1）丝氨酸 579 磷酸化和线粒体分裂。IL-1β 产生依赖于活性氧（ROS）的产生，并且 DRP1 磷酸化导致 NLRP3 炎症小体的上调。此外，受体相互作用蛋白激酶 1（RIPK1）的激酶活性对于 IL-1β 产生和 RIPK1-DRP1 关联是必需的，这表明 RIPK1 是 DRP1 磷酸化的上游激酶。我们的结果揭示了 RIPK1/DRP1 信号轴的关键作用，其激活导致线粒体分裂和 ROS 释放，从而调节 SIV 感染的 PAMs 中猪 NLRP3 炎症小体介导的 IL-1β 产生。
