Alpha/beta interferon receptor signaling amplifies early proinflammatory cytokine production in the lung during respiratory syncytial virus infection.
Alpha/beta interferon receptor signaling amplifies early proinflammatory cytokine production in the lung during respiratory syncytial virus infection.
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DOI：
10.1128/jvi.00333-14
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发表时间：
2014-06
影响因子：
5.4
通讯作者：
Johansson C
中科院分区：
文献类型：
--
作者：
Goritzka M;Durant LR;Pereira C;Salek-Ardakani S;Openshaw PJ;Johansson C
I型干扰素（IFN）在病毒感染后早期产生，并通过α/β干扰素（IFN-α/β）受体（IFNAR）发出信号以诱导编码对限制病毒复制和指导免疫应答重要的蛋白质的基因。为了研究I型干扰素在气道炎症局部调节中的作用程度，我们研究了它们在呼吸道合胞病毒（RSV）感染的早期肺反应中的重要性。IFNAR 1缺陷型（IFNAR 1 −/−）小鼠在RSV感染期间表现出肺病毒载量增加和体重减轻。正如预期的那样，IFN诱导基因的表达在IFNAR 1 −/−小鼠的肺中显著减少。令人惊讶的是，我们发现在缺乏IFNAR信号的情况下，RSV感染小鼠肺部的促炎细胞因子和趋化因子水平也大大降低。此外，在用非感染性先天免疫刺激物（如选定的Toll样受体（TLR）激动剂）激发的IFNAR 1 −/−小鼠的肺部也检测到低水平的促炎细胞因子。最后，重组IFN-α足以增强先天免疫刺激激发的野生型小鼠肺中炎症介质的产生。因此，除了其在抗病毒抗性中的众所周知的作用之外，I型IFN受体信号传导还充当肺中早期促炎反应的中心驱动器。因此，抑制I型IFN的作用可用于抑制以增强的炎性细胞因子产生为特征的肺部疾病中的炎症。重要性病毒感染的初始反应的特征是产生干扰素（IFN）。一组IFN（I型IFN）在病毒感染后早期产生，并通过IFN-α/β受体（IFNAR）发出信号以诱导对于限制病毒复制和指导免疫应答重要的蛋白质。在这里，我们研究了I型干扰素在呼吸道合胞病毒（RSV）的早期反应的重要性。我们的数据表明，I型IFN的产生和IFNAR受体信号不仅诱导抗病毒状态，而且还有助于放大呼吸道中的促炎反应。我们也证实了这一结论，在另一个模型的急性炎症诱导的非感染性刺激。我们的发现与人类疾病相关，因为RSV是婴儿细支气管炎的主要原因，并且已知IFN系统中的多态性影响疾病的严重程度。
Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-α/β) receptor (IFNAR) to induce genes that encode proteins important for limiting viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1−/−) mice displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1−/− mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1−/− mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-α was sufficient to potentiate the production of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases characterized by enhanced inflammatory cytokine production. IMPORTANCE The initial response to viral infection is characterized by the production of interferons (IFNs). One group of IFNs, the type I IFNs, are produced early upon virus infection and signal through the IFN-α/β receptor (IFNAR) to induce proteins important for limiting viral replication and directing immune responses. Here we examined the importance of type I IFNs in early responses to respiratory syncytial virus (RSV). Our data suggest that type I IFN production and IFNAR receptor signaling not only induce an antiviral state but also serve to amplify proinflammatory responses in the respiratory tract. We also confirm this conclusion in another model of acute inflammation induced by noninfectious stimuli. Our findings are of relevance to human disease, as RSV is a major cause of infant bronchiolitis and polymorphisms in the IFN system are known to impact disease severity.