High Expression of IL-36γ in Influenza Patients Regulates Interferon Signaling Pathway and Causes Programmed Cell Death During Influenza Virus Infection.
High Expression of IL-36γ in Influenza Patients Regulates Interferon Signaling Pathway and Causes Programmed Cell Death During Influenza Virus Infection.
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DOI：
10.3389/fimmu.2020.552606
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发表时间：
2020
影响因子：
7.3
通讯作者：
Cao B
中科院分区：
文献类型：
--
作者：
Liu S;Li H;Wang Y;Li H;Du S;Zou X;Zhang X;Cao B
急性呼吸窘迫综合征（ARDS）是流感感染的严重并发症，发病率和死亡率较高。尽管IL-36γ已被证明可促进上皮部位的炎症并防止特定病原体感染，但其在严重流感感染中的具体作用仍知之甚少。在本研究中，我们发现IL-36γ在流感诱导的ARDS患者中的表达高于健康个体。甲型流感病毒（Influenza A virus， IAV）在人肺上皮细胞和外周血单个核细胞中诱导IL-36γ，其诱导与环氧合酶-2 (COX-2)/前列腺素E2 （PGE2）轴的启动有协同关系。我们还发现，在严重流感患者和iav刺激细胞中，浅表IL-36R的表达升高。此外，尽管IL-36γ增强了I型和III型干扰素（ifn）的诱导，从而促进iav介导的ifn刺激的肺上皮细胞中STAT1和STAT2磷酸化抑制，但下游干扰素刺激基因（ISGs）不受影响。最后，我们发现IL-36γ可以促进IAV感染早期的细胞凋亡和抑制自噬。总之，这些发现表明IL-36γ是应答IAV感染的关键宿主免疫因子。它在干扰素信号通路的调控中具有潜在的活性，并参与了人气道上皮细胞不同类型的程序性细胞死亡。
As a severe complication of influenza infection, acute respiratory distress syndrome (ARDS) has higher morbidity and mortality. Although IL-36γ has been proven to promote inflammation at epithelial sites and protect against specific pathogen infection, the detailed roles in severe influenza infection remain poorly understood. In this study, we have found that the expression of IL-36γ is higher in influenza-induced ARDS patients than healthy individuals. IL-36γ was induced in human lung epithelial cells and peripheral blood mononuclear cells by Influenza A virus (IAV) infection, and its induction was synergistically correlated with initiation of the cyclooxygenase-2 (COX-2)/Prostaglandin E2 (PGE2) axis. We also have found that expression of superficial IL-36R was elevated in severe influenza patients and in IAV-stimulated cells. Furthermore, although IL-36γ enhanced the induction of type I and III interferons (IFNs), which promoted IAV-mediated IFN-stimulated STAT1 and STAT2 phosphorylated inhibition in lung epithelial cells, the downstream interferon-stimulated genes (ISGs) were not affected. Finally, we have revealed that IL-36γ treatment could promote apoptosis and inhibit autophagy in the early stages of IAV infection. Overall, these findings demonstrated IL-36γ is a critical host immune factor in response to IAV infection. It has potential activity in the regulation of the interferon signaling pathway and was involved in different types of programmed cell death in human airway epithelial cells as well.