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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

2018; Elsevier BV; Volume: 143; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2018.05.026

1097-6825

Zala Jevnikar, Jörgen Östling, Elisabeth Ax, Jenny Calvén, Kristofer Thörn, Elisabeth Israelsson, Lisa Öberg, Akul Singhania, Laurie C.K. Lau, Susan J. Wilson, Jonathan Ward, Anoop Chauhan, Ana R. Sousa, Bertrand De Meulder, Matthew J. Loza, Frédéric Baribaud, Peter J. Sterk, Kian Fan Chung, Kai Sun, Yike Guo, Ian M. Adcock, Debbie Payne, Barbro Dahlén, Pascal Chanez, Dominick Shaw, Norbert Krug, Jens M. Hohlfeld, Thomas Sandström, Ratko Djukanović, Anna James, Timothy S.C. Hinks, Peter Howarth, Outi Vaarala, Marleen van Geest, Henric Olsson, Ian M. Adcock, Hassan Ahmed, Charles Auffray, Per Bakke, Aruna T. Bansal, Frédéric Baribaud, Stewart Bates, Elisabeth H. Bel, Jeanette Bigler, Hans Bisgaard, Michael Boedigheimer, Klaus Bønnelykke, Joost Brandsma, Paul Brinkman, Enrica Bucchioni, Dominic Burg, Andrew Bush, Massimo Caruso, Amphun Chaiboonchoe, Pascal Chanez, F.K. Chung, C. Compton, Julie Corfield, A. D’Amico, Sven‐Erik Dahlén, Bertrand De Meulder, Ratko Djukanović, V.J. Erpenbeck, Damijan Eržen, K. Fichtner, Neil Fitch, Louise Fleming, E. Formaggio, Stephen J. Fowler, Urs Frey, Martina Gahlemann, Thomas Geiser, Victoria Goss, Yike Guo, Simone Hashimoto, John Haughney, Gunilla Hedlin, Pieter‐Paul Hekking, Tim Higenbottam, Jens M. Hohlfeld, Cécile Holweg, Ildikó Horváth, A.J. James, Richard Knowles, Alan J. Knox, N. Krug, Diane Lefaudeux, Matthew J. Loza, Alexander Manta, J.G. Matthews, Alexander Mazein, Andrea Meiser, Roelinde Middelveld, M. Miralpeix, Paolo Montuschi, Nadia Mores, Clare Murray, J. Musial, David Myles, Laurie Pahus, Ioannis Pandis, Stelios Pavlidis, Anthony D. Postle, P. Powel, G. Praticò, Navin Rao, J. Riley, Amanda Roberts, Graham Roberts, Anthony Rowe, Thomas Sandström, James Schofield, Wolfgang Seibold, Anna Selby, Dominick Shaw, Ralf Sigmund, Florian Singer, Paul Skipp, Ana R. Sousa, Peter J. Sterk, Kai Sun, Bob Thornton, W. M. van Aalderen, Marleen van Geest, Jørgen Vestbo, Nadja Hawwa Vissing, Ariane H. Wagener, Scott Wagers, Z. Weiszhart, Craig E. Wheelock, Susan J. Wilson,

Eosinophilic Esophagitis

BackgroundAlthough several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.ObjectiveWe sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.MethodsAn IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of 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 biopsy specimens.ResultsActivation of IL-6TS in air-liquid interface 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 patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the 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 Toll-like receptor pathway genes were upregulated, whereas expression of cell 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, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.ConclusionsLocal lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients. Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of 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 biopsy specimens. Activation of IL-6TS in air-liquid interface 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 patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the 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 Toll-like receptor pathway genes were upregulated, whereas expression of cell 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, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.