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

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Unbiased Biomarkers Prediction Re , Jevnikar , Z , Östling , J & Vaarala , O 2019 , ' Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation ' , Journal of Allergy and Clinical Immunology , vol. 143 , no. 2 , pp. 577-590 . https://doi.org/10.1016/j.jaci.2018.05.026

Title: Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
Author: Unbiased Biomarkers Prediction Re; Jevnikar, Zala; Östling, Jörgen; Vaarala, Outi
Contributor: University of Helsinki, HUS Children and Adolescents
Date: 2019-02
Language: eng
Number of pages: 14
Belongs to series: Journal of Allergy and Clinical Immunology
ISSN: 0091-6749
URI: http://hdl.handle.net/10138/327629
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 1 beta, IL-8, and IL-1 beta. 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.
Subject: Asthma
lung epithelium
transcriptomics
hierarchical clustering
IL-6 signaling
exacerbation frequency
eosinophils
airway inflammation
remodeling
epithelial integrity
CHITINASE-LIKE PROTEIN
INTERLEUKIN-6 RECEPTOR
MATRIX METALLOPROTEINASES
BARRIER FUNCTION
SEVERITY
DISEASE
TARGET
CELLS
HYPERRESPONSIVENESS
DYSFUNCTION
3121 General medicine, internal medicine and other clinical medicine
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