干扰素刺激哮喘基因表达，2型炎症和内质网应激
2017/11/20
摘要
背景和目的：2型炎症的定量研究为哮喘的异质性提供了分子基础。非2型炎症通路导致的哮喘还不是很清楚。本文旨在阐明2型炎症之外的非常规通路。
方法：我们分别对19名未用糖皮质激素的轻度稳定哮喘患者和16名健康人群通过气管刷获得的上皮细胞进行RNA测序。测序结果对比人和病毒基因组。在同一队列中，在301名严重哮喘单独组中，我们用微阵列分析血液基因表达。
结果:在吸入糖皮质激素轻度哮喘的气道刷中，RNA测序产生1379个差异表达基因（FDR <0.01）。通路分析显示2型炎症标志物，干扰素刺激基因（ISG）和内质网（ER）应激相关基因的表达增加。气道上皮ISG表达与2型炎症哮喘或病毒转录物无关，但与FEV1的肺功能降低有关（ρ= -0.72，p = 0.0004）。通过轻度哮喘中XBP1剪接的增加证实内质网应激，并且与2型炎症和ISG表达相关。ISGs也是哮喘血细胞中最活跃的基因，与气道ISG表达相关（ρ= 0.55 p = 0.030）。 重症哮喘中血液ISG高表达与2型炎症无关。
结论：ISG激活在哮喘中很明显，与病毒转录物无关，与2型炎症正交，并与不同的临床特征相关。内质网应激与2型炎症和ISG表达都相关。
IInterferon-stimulated Gene Expression, Type-2 Inflammation and Endoplasmic Reticulum Stress in Asthma.
Bhakta NR1, Christenson SA2, Nerella S3, Solberg OD4, Nguyen CP5, Choy DF6, Jung KL7, Garudadri S8, Bonser LR9, Pollack JL10, Zlock LT11, Erle DJ12, Langelier C13, Derisi JL14, Arron JR15, Fahy JV16, Woodruff PG17.
Abstract
INTRODUCTION and objectives:Quantification of type-2 inflammation provided a molecular basis for heterogeneity in asthma. Non-type-2 pathways that contribute to asthma pathogenesis are not well understood. To identify dysregulated pathways beyond type-2 inflammation.
METHODS:We applied RNA sequencing to airway epithelial brushings obtained from stable mild asthmatics not on corticosteroids (n=19) and healthy controls (n=16). Sequencing reads were mapped to human and viral genomes. In the same cohort, and in a separate group with severe asthma (n=301), we profiled blood gene expression with microarrays.
RESULTS:In airway brushings from mild asthma on inhaled corticosteroids, RNA sequencing yielded 1379 differentially expressed genes (FDR<0.01). Pathway analysis revealed increased expression of type-2 markers, interferon-stimulated gene (ISGs) and endoplasmic reticulum (ER) stress-related genes. Airway epithelial ISG expression was not associated with type-2 inflammation in asthma or with viral transcripts, but was associated with reduced lung function by FEV1 (ρ=-0.72, p=0.0004). ER stress was confirmed by an increase in XBP1 splicing in mild asthma and was associated with both type-2 inflammation and ISG expression. ISGs were also the most activated genes in blood cells in asthma and were correlated with airway ISG expression (ρ=0.55 p=0.030). High blood ISG expression in severe asthma was similarly unrelated to type-2 inflammation.
CONCLUSIONS:ISG activation is prominent in asthma, independent of viral transcripts, orthogonal to type-2 inflammation, and associated with distinct clinical features. ER stress is associated with both type-2 inflammation and ISG expression.
背景和目的：2型炎症的定量研究为哮喘的异质性提供了分子基础。非2型炎症通路导致的哮喘还不是很清楚。本文旨在阐明2型炎症之外的非常规通路。
方法：我们分别对19名未用糖皮质激素的轻度稳定哮喘患者和16名健康人群通过气管刷获得的上皮细胞进行RNA测序。测序结果对比人和病毒基因组。在同一队列中，在301名严重哮喘单独组中，我们用微阵列分析血液基因表达。
结果:在吸入糖皮质激素轻度哮喘的气道刷中，RNA测序产生1379个差异表达基因（FDR <0.01）。通路分析显示2型炎症标志物，干扰素刺激基因（ISG）和内质网（ER）应激相关基因的表达增加。气道上皮ISG表达与2型炎症哮喘或病毒转录物无关，但与FEV1的肺功能降低有关（ρ= -0.72，p = 0.0004）。通过轻度哮喘中XBP1剪接的增加证实内质网应激，并且与2型炎症和ISG表达相关。ISGs也是哮喘血细胞中最活跃的基因，与气道ISG表达相关（ρ= 0.55 p = 0.030）。 重症哮喘中血液ISG高表达与2型炎症无关。
结论：ISG激活在哮喘中很明显，与病毒转录物无关，与2型炎症正交，并与不同的临床特征相关。内质网应激与2型炎症和ISG表达都相关。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(Am J Respir Crit Care Med. 2017 Oct 24. doi: 10.1164/rccm.201706-1070OC. [Epub ahead of print])
(Am J Respir Crit Care Med. 2017 Oct 24. doi: 10.1164/rccm.201706-1070OC. [Epub ahead of print])
IInterferon-stimulated Gene Expression, Type-2 Inflammation and Endoplasmic Reticulum Stress in Asthma.
Bhakta NR1, Christenson SA2, Nerella S3, Solberg OD4, Nguyen CP5, Choy DF6, Jung KL7, Garudadri S8, Bonser LR9, Pollack JL10, Zlock LT11, Erle DJ12, Langelier C13, Derisi JL14, Arron JR15, Fahy JV16, Woodruff PG17.
Abstract
INTRODUCTION and objectives:Quantification of type-2 inflammation provided a molecular basis for heterogeneity in asthma. Non-type-2 pathways that contribute to asthma pathogenesis are not well understood. To identify dysregulated pathways beyond type-2 inflammation.
METHODS:We applied RNA sequencing to airway epithelial brushings obtained from stable mild asthmatics not on corticosteroids (n=19) and healthy controls (n=16). Sequencing reads were mapped to human and viral genomes. In the same cohort, and in a separate group with severe asthma (n=301), we profiled blood gene expression with microarrays.
RESULTS:In airway brushings from mild asthma on inhaled corticosteroids, RNA sequencing yielded 1379 differentially expressed genes (FDR<0.01). Pathway analysis revealed increased expression of type-2 markers, interferon-stimulated gene (ISGs) and endoplasmic reticulum (ER) stress-related genes. Airway epithelial ISG expression was not associated with type-2 inflammation in asthma or with viral transcripts, but was associated with reduced lung function by FEV1 (ρ=-0.72, p=0.0004). ER stress was confirmed by an increase in XBP1 splicing in mild asthma and was associated with both type-2 inflammation and ISG expression. ISGs were also the most activated genes in blood cells in asthma and were correlated with airway ISG expression (ρ=0.55 p=0.030). High blood ISG expression in severe asthma was similarly unrelated to type-2 inflammation.
CONCLUSIONS:ISG activation is prominent in asthma, independent of viral transcripts, orthogonal to type-2 inflammation, and associated with distinct clinical features. ER stress is associated with both type-2 inflammation and ISG expression.
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TH2/TH17优势型与TH2/TH17低型中性粒细胞内型哮喘的机制研究
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