Zala Jevnikar1, Jörgen Östling2, Elisabeth Ax3, Jenny Calvén2, Kristofer Thörn2, Elisabeth Israelsson2, Lisa Öberg2, Akul Singhania4, Laurie C K Lau4, Susan J Wilson5, Jonathan A Ward5, Anoop Chauhan6, Ana R Sousa7, Bertrand De Meulder8, Matthew J Loza9, Frédéric Baribaud9, Peter J Sterk10, Kian Fan Chung11, Kai Sun12, Yike Guo12, Ian M Adcock11, Debbie Payne13, Barbro Dahlen14, Pascal Chanez15, Dominick E Shaw16, Norbert Krug17, Jens M Hohlfeld18, Thomas Sandström19, Ratko Djukanovic20, Anna James21, Timothy S C Hinks22, Peter H Howarth23, Outi Vaarala2, Marleen van Geest2, Henric Olsson2. 1. Department of Bioscience, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. Electronic address: Zala.Rojnik@astrazeneca.com. 2. Department of Bioscience, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. 3. 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. 4. Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, United Kingdom. 5. 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. 6. Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom. 7. Discovery Medicine, GlaxoSmithKline, Brentford, United Kingdom. 8. European Institute for Systems Biology and Medicine, CIRI UMR5308, CNRS-ENS-UCBL-INSERM, Université de Lyon, Lyon, France. 9. Janssen R&D, Johnson & Johnson, Springhouse, Pa. 10. Department of Respiratory Medicine, Academic Medical Center, Amsterdam, The Netherlands. 11. 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. 12. Department of Computing & Data Science Institute, Imperial College London, London, United Kingdom. 13. Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, United Kingdom. 14. Karolinska University Hospital & Centre for Allergy Research, Karolinska Institute, Stockholm, Sweden. 15. Université de la Méditerranée, Marseille, France. 16. Respiratory Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom. 17. Fraunhofer Institute of Toxicology and Experimental Medicine, Member of the German Center for Lung Research, Hannover, Germany. 18. 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. 19. Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden. 20. NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom. 21. Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. 22. 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. 23. 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.
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.
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.
Authors: Daniel J Jackson; Leonard B Bacharier; Agustin Calatroni; Michelle A Gill; Jack Hu; Andrew H Liu; Lisa M Wheatley; James E Gern; Rebecca S Gruchalla; Gurjit K Khurana Hershey; Meyer Kattan; Carolyn M Kercsmar; Haejin Kim; George T O'Connor; Shilpa Patel; Jacqueline A Pongracic; Robert A Wood; William W Busse Journal: J Allergy Clin Immunol Date: 2020-01-28 Impact factor: 10.793
Authors: Juliana Durack; Laura S Christian; Snehal Nariya; Jeanmarie Gonzalez; Nirav R Bhakta; K Mark Ansel; Avraham Beigelman; Mario Castro; Anne-Marie Dyer; Elliot Israel; Monica Kraft; Richard J Martin; David T Mauger; Stephen P Peters; Sharon R Rosenberg; Christine A Sorkness; Michael E Wechsler; Sally E Wenzel; Steven R White; Susan V Lynch; Homer A Boushey; Yvonne J Huang Journal: J Allergy Clin Immunol Date: 2020-04-13 Impact factor: 10.793
Authors: Eunice Y Lee; Angel C Y Mak; Donglei Hu; Satria Sajuthi; Marquitta J White; Kevin L Keys; Walter Eckalbar; Luke Bonser; Scott Huntsman; Cydney Urbanek; Celeste Eng; Deepti Jain; Gonçalo Abecasis; Hyun M Kang; Soren Germer; Michael C Zody; Deborah A Nickerson; David Erle; Elad Ziv; Jose Rodriguez-Santana; Max A Seibold; Esteban G Burchard Journal: Am J Respir Crit Care Med Date: 2020-10-01 Impact factor: 21.405
Authors: Katherine E Menson; Madeleine M Mank; Leah F Reed; Camille J Walton; Katherine E Van Der Vliet; Jennifer L Ather; David G Chapman; Bradford J Smith; Mercedes Rincon; Matthew E Poynter Journal: Am J Physiol Lung Cell Mol Physiol Date: 2020-08-12 Impact factor: 5.464