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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; 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 K.

Authors

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

Ana R. Sousa

Bertrand De Meulder

Matthew J. Loza

Frédéric Baribaud

Peter J. Sterk

Kian Fan Chung

Kai Sun

Yike Guo

Ian M. Adcock

Debbie Payne

Barbro Dahlen

Pascal Chanez

Norbert Krug

Jens M. Hohlfeld

Thomas Sandström

Ratko Djukanovic

Anna James

Timothy S.C. Hinks

Peter H. Howarth

Outi Vaarala

Marleen van Geest

Henric K. Olsson



Abstract

Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) with asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthma is unclear.
Objective: To explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthma.
Methods: An IL-6TS gene signature, obtained from air-liquid interface (ALI) cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R, was used to stratify lung epithelium transcriptomic data (U-BIOPRED cohorts) by 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 biopsies.
Results: Activation of IL-6TS in ALI 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 IL-6TS. High asthma patients with increased epithelial expression of IL-6TS inducible genes in 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, TLR pathway genes were up-regulated while the expression of tight 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, MMP3, MIP-1β, IL-8 and IL-1β.
Conclusions: Local lung epithelial IL-6TS activation in absence of type 2 airway inflammation defines a novel subset of asthmatics and may drive airway inflammation and epithelial dysfunction in these patients.

Citation

Jevnikar, Z., Östling, J., Ax, E., Calvén, J., Thörn, K., Israelsson, E., …Olsson, H. K. (in press). Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. Journal of Allergy and Clinical Immunology, https://doi.org/10.1016/j.jaci.2018.05.026

Journal Article Type Article
Acceptance Date May 4, 2018
Online Publication Date Jun 11, 2018
Deposit Date Jun 14, 2018
Publicly Available Date Jun 14, 2018
Journal Journal of Allergy and Clinical Immunology
Print ISSN 0091-6749
Electronic ISSN 0091-6749
Publisher Elsevier
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1016/j.jaci.2018.05.026
Keywords Asthma, lung epithelium, transcriptomics, hierarchical clustering, IL-6 signaling, exacerbation frequency, eosinophils, airway inflammation, remodeling, epithelial integrity
Public URL http://eprints.nottingham.ac.uk/id/eprint/52416
Publisher URL https://www.jacionline.org/article/S0091-6749(18)30847-9/abstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0


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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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