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

Jevnikar, Zala; Östling, Jörgen; Ax, Elisabeth; Calvén, Jenny; Thörn, Kristofer; Israelsson, Elisabeth; Öberg, Lisa; Singhania, Akul; Lau, Laurie C.K.; Wilson, Susan J.; Ward, Jonathan A.; Chauhan, Anoop; Sousa, Ana R.; De Meulder, Bertrand; Loza, Matthew J.; Baribaud, Frédéric; Sterk, Peter J.; Chung, Kian Fan; Sun, Kai; Guo, Yike; Adcock, Ian M.; Payne, Debbie; Dahlen, Barbro; Chanez, Pascal; Shaw, Dominick E.; Krug, Norbert; Hohlfeld, Jens M.; Sandström, Thomas; Djukanovic, Ratko; James, Anna; Hinks, Timothy S.C.; Howarth, Peter H.; Vaarala, Outi; van Geest, Marleen; Olsson, Henric K.

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.

Citation

Jevnikar, Z., Östling, J., Ax, E., Calvén, J., Thörn, K., Israelsson, E., Öberg, L., Singhania, A., Lau, L. C., Wilson, S. J., Ward, J. A., Chauhan, A., Sousa, A. R., De Meulder, B., Loza, M. J., Baribaud, F., Sterk, P. J., Chung, K. F., Sun, K., Guo, Y., …Olsson, H. K. (2019). Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. Journal of Allergy and Clinical Immunology, 143(2), 577-590. https://doi.org/10.1016/j.jaci.2018.05.026

• Journal Article Type: Article
• Acceptance Date: May 4, 2018
• Online Publication Date: Jun 11, 2018
• Publication Date: 2019-02
• Deposit Date: Jun 14, 2018
• Publicly Available Date: Jun 14, 2018
• Journal: Journal of Allergy and Clinical Immunology
• Print ISSN: 0091-6749
• Electronic ISSN: 1097-6825
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 143
• Issue: 2
• Pages: 577-590
• DOI: https://doi.org/10.1016/j.jaci.2018.05.026
• Keywords: Asthma, lung epithelium, transcriptomics, hierarchical clustering, IL-6 signaling, exacerbation frequency, eosinophils, airway inflammation, remodeling, epithelial integrity
• Public URL: https://nottingham-repository.worktribe.com/output/937322
• Publisher URL: https://www.jacionline.org/article/S0091-6749(18)30847-9/abstract
• Additional Information: This article is maintained by: Elsevier; Article Title: Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation; Journal Title: Journal of Allergy and Clinical Immunology; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jaci.2018.05.026; Content Type: article; Copyright: © 2018 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.
• Contract Date: Jun 14, 2018