A critical role of Gas6/Axl signal in allergic airway responses during RSV vaccine-enhanced disease
A critical role of Gas6/Axl signal in allergic airway responses during RSV vaccine-enhanced disease
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DOI：
10.1038/icb.2017.61
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发表时间：
2017-11-01
影响因子：
4
通讯作者：
Ato, Manabu
中科院分区：
文献类型：
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作者：
Shibata, Takehiko;Ato, Manabu
呼吸道合胞病毒（RSV）是一种常见的病毒，可导致各种年龄段的下呼吸道感染。没有获得许可的RSV疫苗，因为用福尔马林灭活的RSV（FI-RSV）接种和随后的RSV感染不仅导致中和抗体的诱导不足，而且导致严重的过敏性气道反应，称为FI-RSV疫苗增强疾病（FI-RSV VED）。然而，尽管已知Th 2偏向的免疫反应是这种疾病的标志，但其潜在机制尚未确定。我们以前的研究表明，生长抑制特异性6（Gas6）/Axl信号转导导致真菌诱导的过敏性气道炎症过程中的Th2偏向的免疫反应。在这里，我们表明Gas6/Axl信号传导也导致FI-RSV VED，并在小鼠中部分确定了机制。使用Gas6缺陷小鼠、中和抗体和Axl的特异性抑制剂抑制Gas6/Axl信号传导，除了增加干扰素-γ水平和FI-RSV VED中RSV中和IgG2a的产生之外，还减弱了过敏性气道高反应性，包括气道炎症、杯状细胞增生和Th2细胞因子产生。Gas6在用FI-RSV免疫期间在淋巴结中产生。来自免疫小鼠的淋巴结细胞在用RSV再刺激后产生高水平的Gas6和Th2细胞因子，但不产生IFN-γ。最后，我们发现用RSV-糖蛋白（G蛋白）刺激的树突状细胞产生Gas 6，并且Axl信号传导抑制DC成熟和由Toll样受体4激动剂RSV-融合蛋白诱导的IL-12产生。总之，这些结果表明，RSV-G蛋白诱导的Gas6/Axl信号传导在FI-RSV VED期间引起过敏性气道反应。
Respiratory syncytial virus (RSV) is a common virus that causes lower respiratory infections across a wide range of ages. A licensed RSV vaccine is not available because vaccination with formalin-inactivated RSV (FI-RSV) and the subsequent RSV infection cause not only insufficient induction of neutralizing antibodies but also severe allergic airway responses, termed FI-RSV vaccine-enhanced disease (FI-RSV VED). However, the underlying mechanism has not been identified, although a Th2-biased immune response is known to be a hallmark of this disease. Our previous studies have shown that growth arrest-specific 6 (Gas6)/Axl signaling leads to Th2-biased immune responses during fungus-induced allergic airway inflammation. Here, we show that Gas6/Axl signaling also leads to FI-RSV VED and partially identify the mechanism in mice. Inhibiting Gas6/Axl signaling using Gas6-deficient mice, neutralizing antibodies, and a specific inhibitor of Axl attenuated allergic airway hyperresponsiveness, including airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, in addition to increasing interferon-gamma levels and the production of RSV-neutralizing IgG2a in FI-RSV VED. Gas6 was produced in lymph nodes during immunization with FI-RSV. Lymph node cells derived from immunized mice produced high levels of Gas6 and Th2 cytokines, but not IFN-gamma, after restimulation with RSV. Finally, we found that dendritic cells stimulated with RSV-glycoprotein (G protein) produced Gas6 and that Axl signaling suppressed DC maturation and the induction of IL-12 production by the toll-like receptor 4 agonist RSV-fusion protein. Taken together, these results indicate that RSV-G protein-induced Gas6/Axl signaling causes allergic airway responses during FI-RSV VED.