IFN-stimulated Genes and Non-Type 2 Inflammation. New Pathway or Red Herring?
IFN-stimulated Genes and Non-Type 2 Inflammation. New Pathway or Red Herring?
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DOI：
10.1164/rccm.201710-2144ed
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发表时间：
2017-11
影响因子：
24.7
通讯作者：
Sunita Sharma;F. Holguin
中科院分区：
文献类型：
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作者：
Sunita Sharma;F. Holguin
哮喘是一种异质性疾病，由许多复杂的疾病内在型组成，具有不同的基础病理生理机制、自然史和治疗反应。先前在气道上皮中的基因表达研究证实了轻度哮喘受试者气道中2型（T2）炎症基因的富集，并确定这些基因与气道反应性、IgE水平和嗜酸性粒细胞炎症增加相关（1，2）。T2基因是几种哮喘内源型发展的组成部分，也是治疗严重哮喘的新生物制剂的靶点（1）。然而，越来越多的证据表明，大约一半的哮喘患者患有非T2介导的气道炎症，因此不能从吸入性皮质类固醇（ICS）或新的生物制剂中获益（2-4）。尽管这些个体的痰液中性粒细胞可能增加（3，5），但并非在所有非T2哮喘内型中发现这种增加，这强调了我们对区分这些内型的非T2炎症机制的理解有限的事实。在本期杂志中，Bhakta及其同事（pp. 313-324）报告了他们对IFN刺激基因（ISG）和T2炎症之间关系的分析，并描述了ISG对轻度哮喘受试者肺功能和支气管扩张剂反应的影响（6）。使用轻度哮喘受试者和健康对照受试者气道上皮细胞的RNA测序数据，作者证实了先前的分析，其中确定了已知T2基因的差异表达。此外，使用独创性途径分析来阐明过度表达基因的上游调节因子，作者确定了一组在哮喘受试者气道中富集的ISG。他们的ISG签名在轻度哮喘受试者与健康对照受试者相比的气道上皮和IFN-α刺激后培养的人支气管上皮细胞中差异表达。作者证明，在轻度哮喘受试者中，较高的ISG表达与FEV 1降低和支气管扩张剂反应增加相关，这些相关性与T2炎症无关。此外，ICS治疗总体上减弱了ISG与FEV 1和ISG表达降低的相关性。然而，轻度和重度哮喘患者全血中的ISG特征与FEV 1或皮质类固醇治疗无关。这项研究有几个优势，使其成为一个重要的除了迅速增长的文献非T2途径在哮喘。首先，它加强了T辅助细胞1型（Th 1）途径，包括ISG，是轻度哮喘患者非T2炎症的重要调节因子的论点。目前的工作结果扩展了先前在小鼠模型中的研究，该研究表明IFN-g与气道反应性增加相关（7）。人体研究还显示，与对照组相比，特应性哮喘受试者支气管活检标本中IFN-g表达增加（8），与轻度至中度哮喘受试者相比，重度哮喘受试者BAL液中CD 4 + T细胞百分比更高，IFN-g表达增加，IFN-g蛋白水平更高（7）。这项研究的结果还提供了进一步的证据，T1通路可以独立于T2炎症影响哮喘发病机制，并且与严重哮喘研究计划的最新发现相似。通过对严重哮喘患者气道上皮细胞进行加权基因共表达网络分析，他们确定了...
Asthma is a heterogeneous disease comprised of numerous complex disease endotypes with different underlying pathophysiologic mechanisms, natural histories, and treatment responses. Previous geneexpression studies in airway epithelium demonstrated an enrichment of type 2 (T2) inflammatory genes in the airways of subjects with mild asthma, and identified that these genes are associated with increased airway responsiveness, IgE levels, and eosinophilic inflammation (1, 2). T2 genes are integral to the development of several asthma endotypes and are the targets of new biologic agents for severe asthma (1). There is, however, growing evidence that roughly half of individuals with asthma have non–T2-mediated airway inflammation and thus do not benefit from inhaled corticosteroids (ICS) or the new biologic agents (2–4). Although sputum neutrophils may be increased in these individuals (3, 5), such an increase is not found in all non-T2 asthma endotypes, underscoring the fact that our understanding of the non-T2 inflammatory mechanisms that differentiate these endotypes is limited. In this issue of the Journal, Bhakta and colleagues (pp. 313–324) report their analysis of the relationship between IFN-stimulated genes (ISGs) and T2 inflammation, and describe the impact of ISGs on lung function and bronchodilator response in subjects with mild asthma (6). Using RNA-sequencing data from airway epithelial cells of subjects with mild asthma and healthy control subjects, the authors confirmed previous analyses in which differential expression of known T2 genes was identified. In addition, using ingenuity pathway analysis to elucidate the upstream regulators of the overrepresented genes, the authors identified a set of ISGs that were enriched in the airways of subjects with asthma. Their ISG signature was differentially expressed both in the airway epithelium of subjects with mild asthma compared with healthy control subjects and in cultured human bronchial epithelial cells after IFN-a stimulation. The authors demonstrated that higher ISG expression was associated with reduced FEV1 and increased bronchodilator response in subjects with mild asthma and that these associations were independent of T2 inflammation. Furthermore, the association of ISG with decreased FEV1 and ISG expression overall was attenuated by ICS treatment. However, the ISG signature in the whole blood of individuals with both mild and severe asthma was not associated with FEV1 or treatment with corticosteroids. This study has several strengths that make it a significant addition to the rapidly growing literature on non-T2 pathways in asthma. First, it strengthens the argument that T-helper cell type 1 (Th1) pathways, including ISGs, are important regulators of non-T2 inflammation in individuals with mild asthma. The results of the current work extend previous investigations in mouse models that showed that IFN-g is associated with increased airway responsiveness (7). Human studies have also shown increasedIFN-g expression in bronchial biopsy specimens from subjects with atopic asthma compared with control subjects (8) and a higher percentage of CD4+ T cells, increased IFN-g expression, and higher IFN-g protein levels in the BAL fluid of subjects with severe asthma compared with subjects with mild to moderate asthma (7). The results of this study also provide further evidence that T1 pathways can influence asthma pathogenesis independently of T2 inflammation, and are similar to recent findings from the Severe Asthma Research Program. Using weighted gene coexpression network analysis in airway epithelium from subjects with severe asthma, they identified …