Decreased expression of airway epithelial Axl is associated with eosinophilic inflammation in severe asthma
Decreased expression of airway epithelial Axl is associated with eosinophilic inflammation in severe asthma
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气道上皮 Axl 表达减少与严重哮喘中的嗜酸性粒细胞炎症相关
DOI：
10.1016/j.alit.2022.02.010
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发表时间：
2022
影响因子：
6.8
通讯作者：
Ichinose Masaka
中科院分区：
文献类型：
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作者：
Itakura Koji;Fujino Naoya;Kamide Yosuke;Saito Ikuo;Yamada Mitsuhiro;Okutomo Koji;Tsukita Yoko;Saito Takuya;Ichikawa Tomohiro;Numakura Tadahisa;Kyogoku Yorihiko;Aizawa Hiroyuki;Ono Yoshinao;Matsumoto Shuichiro;Hussell Tracy;Taniguchi Masami;Ichinose Masaka
背景：气道上皮源性细胞因子在哮喘中引发和延续2型炎症至关重要。然而，人们对这种上皮细胞驱动的炎症反应是如何负调控的了解甚少。我们之前报道了Axl受体酪氨酸激酶在气道上皮基底细胞中表达，并在确定其干细胞身份方面发挥作用。然而，Axl是否以及如何调节气道2型炎症仍然未知。方法：采用免疫荧光染色法比较非哮喘组、轻中度哮喘组和重度哮喘组气道上皮中Axl的表达。我们通过查询支气管内活组织检查中全球基因表达的公共数据库证实了这一结果。然后，我们用屋尘螨提取物（HDM）鼻内处理野生型或axl敲除小鼠，并对其气管内浸润的嗜酸性粒细胞数量进行量化。利用靶向Axl的siRNA进一步进行基于细胞的检测，以鉴定参与Axl介导的炎症调节的分子。结果：组织学分析和转录组学分析显示，重症哮喘患者气道基底细胞中Axl蛋白和mRNA表达减少。Axl表达的减少与严重哮喘患者嗜酸性粒细胞和肥大细胞的浸润有关。重复给药后，axl基因敲除小鼠气管内嗜酸性粒细胞的浸润更为明显。sirna介导的Axl敲除上调人支气管上皮细胞中粒细胞巨噬集落刺激因子（GM-CSF） mRNA和蛋白的表达。结论：基底细胞表达的Axl激酶可能通过抑制气道GM-CSF抑制过度嗜酸性粒细胞炎症。Axl减少对严重哮喘的发病机制有临床意义。
Background: Airway epithelium-derived cytokines are critical to provoke and perpetuate type 2 inflammation in asthma. Yet it is poorly understood how this epithelial cell-driven inflammatory response is negatively regulated. We previously reported that Axl receptor tyrosine kinase was expressed by basal cells in the airway epithelium and had a role in defining their stem cell identity. However, whether and how Axl regulates airway type 2 inflammation remains unknown.Methods: We performed immunofluorescence staining to compare Axl expression in airway epithelium between non-asthmatic subjects, mild-moderate asthma and severe asthma. We confirmed this result by interrogating public databases of global gene expression in endobronchial biopsies. We then quantified eosinophil numbers infiltrating into the trachea of wild-type or Axl-knockout mice that were intranasally treated with house dust mite extracts (HDM). Cell-based assays using siRNA targeting Axl were further performed to identify molecules involved in Axl-mediated regulation of inflammation.Results: Histological assessments and transcriptome analyses revealed decreases in protein and mRNA of Axl in airway basal cells of severe asthmatics. This reduction of Axl expression was correlated with infiltration of eosinophils and mast cells in severe asthmatics. Eosinophil infiltration was more evident in the trachea of Axl-knockout mice in response to repetitive HDM administration. siRNA-mediated knockdown of Axl increased mRNA and protein expression of granulocyte macrophage-colony stimulating factor (GM-CSF) in human bronchial epithelial cells.Conclusions: Axl kinase expressed by basal cells may suppress excessive eosinophilic inflammation via inhibition of GM-CSF in the airway. Axl reduction has clinical implications for the pathogenesis of severe asthma.