Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
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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, Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes study group
Аннотация
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.