哮喘易感基因Gasdermin B促进MAVS-TBK1信号传导和气道炎症
2024/05/28
摘要
背景：呼吸道病毒诱发炎症反应是哮喘恶化的主要原因，常伴有干扰素刺激基因（ISG）激活。在遗传易感哮喘患者中，哮喘易感基因如何通过微调ISG激活和后续气道炎症进而调节病毒感染后的细胞反应，目前尚不清楚。
目的：本研究旨在探究gasdermin B（由GSDMB编码）在呼吸道病毒诱导肺部炎症中的作用。
方法：本研究分析了两个独立的队列中，GSDMB和ISG之间表达的相关性。本研究采用人类支气管上皮细胞系或原代支气管上皮细胞，构建GSDMB-过表达和GSDMB-缺陷细胞，并进行了一系列定量PCR、ELISA和免疫共沉淀测定，以确定GSDMB诱导ISG的功能和机制。本研究同时构建了一种新的转基因小鼠系，即在气道上皮细胞中可诱导表达人类特异性GSDMB基因，并通过采用呼吸道合胞病毒感染小鼠以确定GSDMB在呼吸道合胞体病毒诱导的体内肺部炎症中的作用。
结果：GSDMB是17q21最重要的哮喘易感基因之一，并可作为一种新的RNA传感器，促进线粒体抗病毒信号蛋白（MAVS）-TANK结合激酶1（TBK1）信号传导及后续炎症反应。在气道上皮中，GSDMB是由呼吸道病毒感染诱导的。GSDMB和ISG在两个独立哮喘队列的呼吸上皮中的表达显著相关。值得注意的是，人GSDMB在小鼠气道上皮中的诱导表达导致ISG诱导增强，并在呼吸道合胞病毒感染后增加气道炎症和粘液高分泌。
结论：GSDMB在呼吸道病毒感染时促进ISGs的表达和气道炎症，从而增加风险等位基因携带者的哮喘风险。
Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation.
Liu T, Liu S, Rui X, Cao Y, Hecker J, Guo F, Zhang Y, Gong L, Zhou Y, Yu Y, Krishnamoorthyni N, Bates S, Chun S, Boyer N, Xu S, Park JA, Perrella MA, Levy BD, Weiss ST, Mou H, Raby BA, Zhou X.
Abstract
BACKGROUND:Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes (ISGs). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning ISG induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown.
OBJECTIVE:To decipher the functions of gasdermin B (encoded by GSDMB) in respiratory virus-induced lung inflammation.
METHODS:In two independent cohorts, we analysed expression correlation between GSDMB and ISG s. In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated GSDMB-overexpressing and GSDMB-deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISG induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of GSDMB in respiratory syncytial virus-induced lung inflammation in vivo.
RESULTS:GSDMB is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB in mouse airway epithelium led to enhanced ISGs induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection.
CONCLUSION:GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.
背景：呼吸道病毒诱发炎症反应是哮喘恶化的主要原因，常伴有干扰素刺激基因（ISG）激活。在遗传易感哮喘患者中，哮喘易感基因如何通过微调ISG激活和后续气道炎症进而调节病毒感染后的细胞反应，目前尚不清楚。
目的：本研究旨在探究gasdermin B（由GSDMB编码）在呼吸道病毒诱导肺部炎症中的作用。
方法：本研究分析了两个独立的队列中，GSDMB和ISG之间表达的相关性。本研究采用人类支气管上皮细胞系或原代支气管上皮细胞，构建GSDMB-过表达和GSDMB-缺陷细胞，并进行了一系列定量PCR、ELISA和免疫共沉淀测定，以确定GSDMB诱导ISG的功能和机制。本研究同时构建了一种新的转基因小鼠系，即在气道上皮细胞中可诱导表达人类特异性GSDMB基因，并通过采用呼吸道合胞病毒感染小鼠以确定GSDMB在呼吸道合胞体病毒诱导的体内肺部炎症中的作用。
结果：GSDMB是17q21最重要的哮喘易感基因之一，并可作为一种新的RNA传感器，促进线粒体抗病毒信号蛋白（MAVS）-TANK结合激酶1（TBK1）信号传导及后续炎症反应。在气道上皮中，GSDMB是由呼吸道病毒感染诱导的。GSDMB和ISG在两个独立哮喘队列的呼吸上皮中的表达显著相关。值得注意的是，人GSDMB在小鼠气道上皮中的诱导表达导致ISG诱导增强，并在呼吸道合胞病毒感染后增加气道炎症和粘液高分泌。
结论：GSDMB在呼吸道病毒感染时促进ISGs的表达和气道炎症，从而增加风险等位基因携带者的哮喘风险。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Eur Respir J. 2024 May 2;63(5):2301232. doi: 10.1183/13993003.01232-2023.)
(Eur Respir J. 2024 May 2;63(5):2301232. doi: 10.1183/13993003.01232-2023.)
Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation.
Liu T, Liu S, Rui X, Cao Y, Hecker J, Guo F, Zhang Y, Gong L, Zhou Y, Yu Y, Krishnamoorthyni N, Bates S, Chun S, Boyer N, Xu S, Park JA, Perrella MA, Levy BD, Weiss ST, Mou H, Raby BA, Zhou X.
Abstract
BACKGROUND:Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes (ISGs). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning ISG induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown.
OBJECTIVE:To decipher the functions of gasdermin B (encoded by GSDMB) in respiratory virus-induced lung inflammation.
METHODS:In two independent cohorts, we analysed expression correlation between GSDMB and ISG s. In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated GSDMB-overexpressing and GSDMB-deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISG induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of GSDMB in respiratory syncytial virus-induced lung inflammation in vivo.
RESULTS:GSDMB is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB in mouse airway epithelium led to enhanced ISGs induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection.
CONCLUSION:GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.
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