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

Zala Jevnikar, Jörgen Östling, Elisabeth Ax, Jenny Calvén, Kristofer Thörn, Elisabeth Israelsson, Lisa Öberg, Akul Singhania, Laurie C.k. Lau, Susan J. Wilson, Jonathan A. Ward, Anoop Chauhan, A.r. Sousa, B. De Meulder, Matthew J. Loza, Frédéric Baribaud, Peter J. Sterk, Kian Fan Chung, Kai Sun, Yike GuoI.m. Adcock, Debbie Payne, Barbro Dahlen, Pascal Chanez, D.e. Shaw, N. Krug, J.m. Hohlfeld, Thomas Sandström, R. Djukanovic, Anna James, Timothy S.c. Hinks, Peter H. Howarth, Outi Vaarala, Marleen Van Geest, Henric Olsson, Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes study group

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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.
TidsskriftJournal of Allergy and Clinical Immunology
Udgave nummer2
Sider (fra-til)577–590
StatusUdgivet - feb. 2019
Udgivet eksterntJa



Jevnikar, Z., Östling, J., Ax, E., Calvén, J., Thörn, K., Israelsson, E., Öberg, L., Singhania, A., Lau, L. C. K., 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., ... Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes study group (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