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; ... (2019). Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. Journal of allergy and clinical immunology, 143(2), pp. 577-590. Elsevier 10.1016/j.jaci.2018.05.026

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Pneumologie (Pädiatrie)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Paediatric Pneumology

ISSN:

1097-6825

Publisher:

Elsevier

Language:

English

Submitter:

Romy Melanie Rodriguez Del Rio

Date Deposited:

24 Jan 2020 14:55

Last Modified:

24 Jan 2020 14:55

Publisher DOI:

10.1016/j.jaci.2018.05.026

PubMed ID:

29902480

Additional Information:

U-BIPRED study Group: Singer Florian und Krüger Linn

Uncontrolled Keywords:

Asthma IL-6 signaling airway inflammation eosinophils epithelial integrity exacerbation frequency hierarchical clustering lung epithelium remodeling transcriptomics

BORIS DOI:

10.7892/boris.137495

URI:

https://boris.unibe.ch/id/eprint/137495

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