上皮IL-6跨信号转导定义了一种新的气道炎症增加的哮喘表型
2018/07/09
摘要
背景：虽然有几项研究将高水平的IL-6和可溶性IL-6受体（sIL-6R）与哮喘严重程度和肺功能下降联系起来，但IL-6跨信号转导（IL-6TS）在哮喘中的作用尚不清楚。
目的：探讨上皮细胞IL-6TS通路活化与哮喘分子和临床表型之间的关系。
方法：IL-6TS基因表达特征是由IL-6和sIL-6R刺激的人支气管上皮细胞的气液界面（ALI）培养物获得，该基因表达特征通过分层聚类的方法被用于对肺上皮转录组数据（U-BIOPRED组群）进行分层。使用IL-6TS特异性蛋白质标记物对痰生物标志物数据（Wessex群组）进行分层。分子表型分析基于上皮刷状缘的转录分析，通路分析和支气管活检的免疫组织化学分析。
结果：ALI培养物中IL-6TS的活化降低了上皮的完整性，并诱导产生了气道重塑相关的基因富集的基因表达特征。经IL-6TS表达特征区分出了高IL-6TS哮喘患者亚群，他们在无全身性炎症存在情况下，具有上皮IL-6TS诱导型基因高表达。 高IL-6TS亚群表现为频繁加重者比例高，血液嗜酸性粒细胞高，以及粘膜下T细胞和巨噬细胞浸润增多。在支气管刷状缘，TLR通路基因上调，而紧密连接基因表达减少。痰sIL-6R和IL-6水平与重塑和先天免疫激活的痰标志物，尤其是YKL-40，MMP3，MIP-1β，IL-8和IL-1β相关。
结论：在无2型气道炎症反应的情况下局部肺上皮IL-6TS的激活，定义了哮喘患者中一种新的亚群，并且IL-6TS激活可能驱动这些患者中的气道炎症和上皮功能障碍。
Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Jevnikar Z, Östling J, Ax E, Calvén J, Thörn K, Israelsson E, Öberg L, Singhania A, Lau LCK, Wilson SJ, Ward JA, Chauhan A, Sousa AR, De Meulder B, Loza MJ, Baribaud F, Sterk PJ, Chung KF, Sun K,Guo Y, Adcock IM, Payne D, Dahlen B, Chanez P, Shaw DE, Krug N, Hohlfeld JM, Sandström T, Djukanovic R, James A, Hinks TSC, Howarth PH, Vaarala O, van Geest M, Olsson HK; U-BIOPRED study group.
Abstract
BACKGROUND:Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) with asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthma is unclear.
OBJECTIVE:To explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthma.
METHODS:An IL-6TS gene signature, obtained from air-liquid interface (ALI) cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R, was used to stratify lung epithelium transcriptomic data (U-BIOPRED cohorts) by hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis and immunohistochemical analysis of bronchial biopsies.
RESULTS:Activation of IL-6TS in ALI cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of IL-6TS High asthma patients with increased epithelial expression of IL-6TS inducible genes in absence of systemic inflammation. The IL-6TS High subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings, TLR pathway genes were up-regulated while the expression of tight junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, MMP3, MIP-1β, IL-8 and IL-1β.
CONCLUSIONS:Local lung epithelial IL-6TS activation in absence of type 2 airway inflammation defines a novel subset of asthmatics and may drive airway inflammation and epithelial dysfunction in these patients.
背景：虽然有几项研究将高水平的IL-6和可溶性IL-6受体（sIL-6R）与哮喘严重程度和肺功能下降联系起来，但IL-6跨信号转导（IL-6TS）在哮喘中的作用尚不清楚。
目的：探讨上皮细胞IL-6TS通路活化与哮喘分子和临床表型之间的关系。
方法：IL-6TS基因表达特征是由IL-6和sIL-6R刺激的人支气管上皮细胞的气液界面（ALI）培养物获得，该基因表达特征通过分层聚类的方法被用于对肺上皮转录组数据（U-BIOPRED组群）进行分层。使用IL-6TS特异性蛋白质标记物对痰生物标志物数据（Wessex群组）进行分层。分子表型分析基于上皮刷状缘的转录分析，通路分析和支气管活检的免疫组织化学分析。
结果：ALI培养物中IL-6TS的活化降低了上皮的完整性，并诱导产生了气道重塑相关的基因富集的基因表达特征。经IL-6TS表达特征区分出了高IL-6TS哮喘患者亚群，他们在无全身性炎症存在情况下，具有上皮IL-6TS诱导型基因高表达。 高IL-6TS亚群表现为频繁加重者比例高，血液嗜酸性粒细胞高，以及粘膜下T细胞和巨噬细胞浸润增多。在支气管刷状缘，TLR通路基因上调，而紧密连接基因表达减少。痰sIL-6R和IL-6水平与重塑和先天免疫激活的痰标志物，尤其是YKL-40，MMP3，MIP-1β，IL-8和IL-1β相关。
结论：在无2型气道炎症反应的情况下局部肺上皮IL-6TS的激活，定义了哮喘患者中一种新的亚群，并且IL-6TS激活可能驱动这些患者中的气道炎症和上皮功能障碍。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2018 Jun 11. pii: S0091-6749(18)30847-9.)
(J Allergy Clin Immunol. 2018 Jun 11. pii: S0091-6749(18)30847-9.)
Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Jevnikar Z, Östling J, Ax E, Calvén J, Thörn K, Israelsson E, Öberg L, Singhania A, Lau LCK, Wilson SJ, Ward JA, Chauhan A, Sousa AR, De Meulder B, Loza MJ, Baribaud F, Sterk PJ, Chung KF, Sun K,Guo Y, Adcock IM, Payne D, Dahlen B, Chanez P, Shaw DE, Krug N, Hohlfeld JM, Sandström T, Djukanovic R, James A, Hinks TSC, Howarth PH, Vaarala O, van Geest M, Olsson HK; U-BIOPRED study group.
Abstract
BACKGROUND:Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) with asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthma is unclear.
OBJECTIVE:To explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthma.
METHODS:An IL-6TS gene signature, obtained from air-liquid interface (ALI) cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R, was used to stratify lung epithelium transcriptomic data (U-BIOPRED cohorts) by hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis and immunohistochemical analysis of bronchial biopsies.
RESULTS:Activation of IL-6TS in ALI cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of IL-6TS High asthma patients with increased epithelial expression of IL-6TS inducible genes in absence of systemic inflammation. The IL-6TS High subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings, TLR pathway genes were up-regulated while the expression of tight junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, MMP3, MIP-1β, IL-8 and IL-1β.
CONCLUSIONS:Local lung epithelial IL-6TS activation in absence of type 2 airway inflammation defines a novel subset of asthmatics and may drive airway inflammation and epithelial dysfunction in these patients.
