Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
mBio. 2023 Apr 25;14(2):e0011023. doi: 10.1128/mbio.00110-23. Epub 2023 Feb 28.
Influenza A virus (IAV) triggers multiple programmed cell death pathways, including MLKL-dependent necroptosis, caspase-8-dependent apoptosis, and caspase-1-dependent pyroptosis in myeloid cells. All three pathways share common upstream regulators, namely, ZBP1 and RIPK3. Yet, the molecular mechanism underlying IAV-induced inflammasome activation remains unclear. Here, we demonstrate that MLKL promotes inflammasome activation and IL-1β processing in IAV-infected macrophages. MLKL drives NLRP3 inflammasome activation through potassium efflux. In the absence of the MLKL-inflammasome axis, caspase-8 coordinates the maturation and secretion of IL-1β. MLKL alone is dispensable for host inflammatory responses to IAV in vivo. Taken together, MLKL and caspase-8 serve as redundant mechanisms by which to drive an inflammatory form of cell death in response to an IAV infection. Influenza A virus (IAV) induces multiple types of cell death, which play important roles in the host antiviral responses but can also cause unwanted inflammation and tissue damage. In this study, we dissect the interplay of cell death pathways and demonstrate that macrophages utilize redundant mechanisms to drive an inflammatory form of cell death upon IAV infection. MLKL, the executor of necroptosis, promotes inflammasome activation and pyroptotic cell death. When the MLKL-inflammasome axis is inhibited, cells divert to caspase-8-dependent inflammatory cell death. Our findings advance the current understanding of the innate immune response to IAV infection as well as broader contexts involving multifaceted cell death.
甲型流感病毒（IAV）触发多种程序性细胞死亡途径，包括髓样细胞中依赖 MLKL 的坏死性凋亡、依赖 caspase-8 的细胞凋亡和依赖 caspase-1 的细胞焦亡。这三种途径都有共同的上游调控因子，即 ZBP1 和 RIPK3。然而，IAV 诱导炎性小体激活的分子机制尚不清楚。在这里，我们证明 MLKL 促进 IAV 感染的巨噬细胞中炎性小体的激活和 IL-1β 的加工。MLKL 通过钾离子外流驱动 NLRP3 炎性小体的激活。在没有 MLKL-炎性小体轴的情况下，caspase-8 协调 IL-1β 的成熟和分泌。MLKL 本身对于宿主对 IAV 的体内炎症反应是可有可无的。总之，MLKL 和 caspase-8 是宿主对 IAV 感染产生炎症性细胞死亡的冗余机制。
甲型流感病毒（IAV）诱导多种类型的细胞死亡，这些细胞死亡在宿主抗病毒反应中发挥重要作用，但也可能导致不必要的炎症和组织损伤。在这项研究中，我们剖析了细胞死亡途径的相互作用，并证明巨噬细胞利用冗余机制来驱动 IAV 感染时的炎症性细胞死亡。作为坏死性凋亡执行者的 MLKL 促进炎性小体的激活和细胞焦亡。当抑制 MLKL-炎性小体轴时，细胞转向依赖 caspase-8 的炎症性细胞死亡。我们的研究结果推进了对 IAV 感染的先天免疫反应以及涉及多方面细胞死亡的更广泛背景的理解。
