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

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

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.

Adult, Airway Remodeling, Asthma/immunology, Biomarkers/metabolism, Cells, Cultured, Cohort Studies, Cross-Sectional Studies, Epithelial Cells/physiology, Gene Expression Regulation, Humans, Inflammation/immunology, Interleukin-6/metabolism, Lung/physiology, Male, Phenotype, Receptors, Interleukin-6/metabolism, Respiratory Hypersensitivity, Signal Transduction, Sputum/metabolism, Transcriptome
0091-6749
577-590
Jevnikar, Zala
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Östling, Jörgen
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Ax, Elisabeth
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Calvén, Jenny
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Thörn, Kristofer
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Israelsson, Elisabeth
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Öberg, Lisa
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Singhania, Akul
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Lau, Laurie
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Wilson, Susan
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Ward, Jonathan
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Chauhan, Anoop
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Sousa, Ana
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Meulder, Bertrand
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Loza, Matthew
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Baribaud, Fredereric
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Sterk, Peter
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Chung, K.F.
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Sun, Kai
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Guo, Yike
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Adcock, I.
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Payne, D.
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Dahlén, Barbro
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Chanez, Pascal
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Shaw, Dominick
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Krug, Norbert
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Hohlfeld, Jens
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Sandström, Thomas
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Djukanovic, Ratko
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James, Anna
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Hinks, Timothy
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Howarth, Peter
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Vaarala, Outi
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van Geest, Marleen
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Olsson, Henric
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Skipp, Paul
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U-BIOPRED Consortium
Jevnikar, Zala
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Östling, Jörgen
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Ax, Elisabeth
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Calvén, Jenny
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Thörn, Kristofer
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Israelsson, Elisabeth
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Öberg, Lisa
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Singhania, Akul
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Lau, Laurie
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Wilson, Susan
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Ward, Jonathan
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Chauhan, Anoop
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Sousa, Ana
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Meulder, Bertrand
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Loza, Matthew
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Baribaud, Fredereric
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Sterk, Peter
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Chung, K.F.
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Sun, Kai
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Guo, Yike
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Adcock, I.
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Dahlén, Barbro
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Shaw, Dominick
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Krug, Norbert
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Hohlfeld, Jens
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Sandström, Thomas
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Djukanovic, Ratko
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James, Anna
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Hinks, Timothy
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Howarth, Peter
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Vaarala, Outi
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van Geest, Marleen
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Olsson, Henric
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Skipp, Paul
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Jevnikar, Zala, Östling, Jörgen, Ax, Elisabeth, Calvén, Jenny, Thörn, Kristofer, Israelsson, Elisabeth, Öberg, Lisa, Singhania, Akul, Lau, Laurie, Wilson, Susan, Ward, Jonathan, Chauhan, Anoop, Sousa, Ana, Meulder, Bertrand, Loza, Matthew, Baribaud, Fredereric, Sterk, Peter, Chung, K.F., Sun, Kai, Guo, Yike, Adcock, I., Payne, D., Dahlén, Barbro, Chanez, Pascal, Shaw, Dominick, Krug, Norbert, Hohlfeld, Jens, Sandström, Thomas, Djukanovic, Ratko, James, Anna, Hinks, Timothy, Howarth, Peter, Vaarala, Outi, van Geest, Marleen, Olsson, Henric and Skipp, Paul , U-BIOPRED Consortium (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. (doi:10.1016/j.jaci.2018.05.026).

Record type: Article

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.

Text
IL6 TS UBIOPRED - Accepted Manuscript
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Accepted/In Press date: 4 May 2018
e-pub ahead of print date: 11 June 2018
Published date: February 2019
Keywords: Adult, Airway Remodeling, Asthma/immunology, Biomarkers/metabolism, Cells, Cultured, Cohort Studies, Cross-Sectional Studies, Epithelial Cells/physiology, Gene Expression Regulation, Humans, Inflammation/immunology, Interleukin-6/metabolism, Lung/physiology, Male, Phenotype, Receptors, Interleukin-6/metabolism, Respiratory Hypersensitivity, Signal Transduction, Sputum/metabolism, Transcriptome

Identifiers

Local EPrints ID: 421475
URI: http://eprints.soton.ac.uk/id/eprint/421475
ISSN: 0091-6749
PURE UUID: 18dfc318-3a68-4242-933c-c2904d219be7
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612
ORCID for Paul Skipp: ORCID iD orcid.org/0000-0002-2995-2959

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Date deposited: 13 Jun 2018 16:30
Last modified: 30 Jul 2020 01:31

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Contributors

Author: Zala Jevnikar
Author: Jörgen Östling
Author: Elisabeth Ax
Author: Jenny Calvén
Author: Kristofer Thörn
Author: Elisabeth Israelsson
Author: Lisa Öberg
Author: Akul Singhania
Author: Laurie Lau
Author: Susan Wilson
Author: Jonathan Ward
Author: Anoop Chauhan
Author: Ana Sousa
Author: Bertrand Meulder
Author: Matthew Loza
Author: Fredereric Baribaud
Author: Peter Sterk
Author: K.F. Chung
Author: Kai Sun
Author: Yike Guo
Author: I. Adcock
Author: D. Payne
Author: Barbro Dahlén
Author: Pascal Chanez
Author: Dominick Shaw
Author: Norbert Krug
Author: Jens Hohlfeld
Author: Thomas Sandström
Author: Anna James
Author: Timothy Hinks
Author: Peter Howarth
Author: Outi Vaarala
Author: Marleen van Geest
Author: Henric Olsson
Author: Paul Skipp ORCID iD

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