Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan.
Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
J Virol. 2018 Jun 29;92(14). doi: 10.1128/JVI.00396-18. Print 2018 Jul 15.
Respiratory epithelial cell death by influenza virus infection is responsible for the induction of inflammatory responses, but the exact cell death mechanism is not understood. Here we showed that influenza virus infection induces apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced only in malignant tumor cells infected with influenza virus. In human precancerous respiratory epithelial cells (PL16T), the number of apoptotic cells increased at early phases of infection, but pyroptotic cells were observed at late phases of infection. These findings suggest that apoptosis is induced at early phases of infection but the cell death pathway is shifted to pyroptosis at late phases of infection. We also found that the type I interferon (IFN)-mediated JAK-STAT signaling pathway promotes the switch from apoptosis to pyroptosis by inhibiting apoptosis possibly through the induced expression of the anti-apoptotic gene. Further, the inhibition of JAK-STAT signaling repressed pyroptosis but enhanced apoptosis in infected PL16T cells. Collectively, we propose that type I IFN signaling pathway triggers pyroptosis but not apoptosis in the respiratory epithelial cells in a mutually exclusive manner to initiate proinflammatory responses against influenza virus infection. Respiratory epithelium functions as a sensor of infectious agents to initiate inflammatory responses along with cell death. However, the exact cell death mechanism responsible for inflammatory responses by influenza virus infection is still unclear. We showed that influenza virus infection induced apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced at early phases of infection, but the cell death pathway was shifted to pyroptosis at late phases of infection under the regulation of type I IFN signaling to promote proinflammatory cytokine production. Taken together, our results indicate that the type I IFN signaling pathway plays an important role to induce pyroptosis but represses apoptosis in the respiratory epithelial cells to initiate proinflammatory responses against influenza virus infection.
流感病毒感染导致呼吸道上皮细胞死亡，进而引发炎症反应，但确切的细胞死亡机制尚不清楚。本研究显示，流感病毒感染可诱导正常或癌前状态的人支气管上皮细胞发生凋亡和细胞焦亡。只有感染流感病毒的恶性肿瘤细胞才会发生凋亡。在人癌前呼吸道上皮细胞（PL16T）中，感染早期凋亡细胞数量增加，但在感染晚期观察到细胞焦亡。这些发现表明，感染早期诱导凋亡，但感染晚期细胞死亡途径转向细胞焦亡。我们还发现，I 型干扰素（IFN）介导的 JAK-STAT 信号通路通过诱导抗凋亡基因的表达，可能通过抑制凋亡来促进从凋亡向细胞焦亡的转变。此外，抑制 JAK-STAT 信号通路会抑制感染的 PL16T 细胞中的细胞焦亡，但会增强细胞凋亡。综上所述，我们提出 I 型 IFN 信号通路以相互排斥的方式在呼吸道上皮细胞中触发细胞焦亡而不是凋亡，从而引发针对流感病毒感染的促炎反应。呼吸道上皮细胞作为感染性病原体的传感器，通过细胞死亡引发炎症反应。然而，流感病毒感染引发炎症反应的确切细胞死亡机制仍不清楚。我们发现，流感病毒感染可诱导正常或癌前状态的人支气管上皮细胞发生凋亡和细胞焦亡。在 I 型 IFN 信号通路的调节下，感染早期诱导凋亡，但在感染晚期，细胞死亡途径转向细胞焦亡，以促进促炎细胞因子的产生。总之，我们的研究结果表明，I 型 IFN 信号通路在呼吸道上皮细胞中发挥重要作用，通过诱导细胞焦亡而非抑制凋亡来引发针对流感病毒感染的促炎反应。
