Axl receptor blockade ameliorates pulmonary pathology resulting from primary viral infection and viral exacerbation of asthma.
Axl receptor blockade ameliorates pulmonary pathology resulting from primary viral infection and viral exacerbation of asthma.
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DOI：
10.4049/jimmunol.1302766
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发表时间：
2014-04-15
期刊：
影响因子：
--
通讯作者：
Hogaboam CM
中科院分区：
文献类型：
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作者：
Shibata T;Habiel DM;Coelho AL;Kunkel SL;Lukacs NW;Hogaboam CM
病毒利用Tyro 3、Axl和Mertk（TAM）受体酪氨酸激酶感染和调节各种细胞类型的免疫特性，这导致我们在实验模型中研究TAM受体活化是否影响原发性病毒感染和病毒性哮喘加重。在这些肺特异性模型中，我们观察到Axl是最丰富的诱导TAM受体蛋白。在原发性呼吸道合胞病毒（RSV）感染期间，抗Axl mAb治疗显著增加产生IFN-γ的T细胞和NK细胞的数量，并显著抑制RSV复制和IL-4和IL-13的全肺水平。肺内H1N1感染诱导致死性肺部炎症，但抗Axl mAb治疗感染小鼠显著增加产生IFN-β的巨噬细胞和树突状细胞的数量，并显著抑制中性粒细胞浸润。因此，与IgG对照治疗组相比，在该模型中H1N1感染的致死效应在mAb治疗组中显著降低。靶向Axl还抑制烟曲霉诱导的哮喘模型中的气道高反应性、IL-4和IL-13的产生以及杯状细胞化生。最后，在真菌性哮喘期间用RSV感染小鼠显著加剧了气道炎症、杯状细胞化生和气道重塑，但在该病毒恶化模型中的所有这些特征都通过抗Axl mAb治疗得到改善。总之，这些结果表明Axl在病毒和/或过敏性病理过程中调节肺免疫应答，并且还表明靶向该TAM受体可能在这些感染性疾病中提供新的治疗方法。
Viruses utilize Tyro3, Axl, and Mertk (TAM) receptor tyrosine kinases to infect and modulate the immune properties of various cell types leading us to investigate whether TAM receptor activation impacted primary viral infection and viral exacerbation of asthma in experimental models. In these lung-specific models, we observed that Axl was the most abundantly induced TAM receptor protein. During primary respiratory syncytial virus (RSV) infection, anti-Axl mAb treatment significantly increased the number of IFN-γ-producing T cells and NK cells, and significantly suppressed RSV replication and whole lung levels of IL-4 and IL-13. Intrapulmonary H1N1 infection induced lethal pulmonary inflammation but anti-Axl mAb treatment of infected mice significantly increased the number of IFN-β-producing macrophages and dendritic cells, and significantly suppressed neutrophil infiltration. Consequently, the lethal effect of H1N1 infection in this model was significantly reduced in the mAb-treated group compared with the IgG control-treated group. Targeting Axl also inhibited airway hyperresponsiveness, IL-4 and IL-13 production, and goblet cell metaplasia in an Aspergillus fumigatus-induced asthma model. Finally, infection of mice with RSV during fungal asthma significantly exacerbated airway inflammation, goblet cell metaplasia, and airway remodeling but all of these features in this viral exacerbation model were ameliorated by anti-Axl mAb treatment. Together, these results demonstrate that Axl modulates the pulmonary immune response during viral and/or allergic pathology, and also suggest that targeting this TAM receptor might provide a novel therapeutic approach in these infectious diseases.