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

Department of Bioscience, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. Electronic address: Zala.Rojnik@astrazeneca.com. Department of Bioscience, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. Department of Bioscience, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, United Kingdom. Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, United Kingdom; Histochemistry Research Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom. Discovery Medicine, GlaxoSmithKline, Brentford, United Kingdom. European Institute for Systems Biology and Medicine, CIRI UMR5308, CNRS-ENS-UCBL-INSERM, Université de Lyon, Lyon, France. Janssen R&D, Johnson & Johnson, Springhouse, Pa. Department of Respiratory Medicine, Academic Medical Center, Amsterdam, The Netherlands. National Heart and Lung Institute, Imperial College London, London UK & Royal Brompton Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, United Kingdom. Department of Computing & Data Science Institute, Imperial College London, London, United Kingdom. Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, United Kingdom. Karolinska University Hospital & Centre for Allergy Research, Karolinska Institute, Stockholm, Sweden. Université de la Méditerranée, Marseille, France. Respiratory Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom. Fraunhofer Institute of Toxicology and Experimental Medicine, Member of the German Center for Lung Research, Hannover, Germany. Fraunhofer Institute of Toxicology and Experimental Medicine, Member of the German Center for Lung Research, Hannover, Germany; Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany. Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden. NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom. Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom; Respiratory Medicine Unit, NDM Experimental Medicine, University of OxfordJohn Radcliffe Hospital, Oxford, United Kingdom. Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.

The Journal of allergy and clinical immunology. 2019;(2):577-590
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Abstract

BACKGROUND 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. OBJECTIVE We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. METHODS 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. RESULTS 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. CONCLUSIONS 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.

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Publication Type : Observational Study

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