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) 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Elsevier
2018
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| Online Access: | https://eprints.nottingham.ac.uk/52416/ |
| _version_ | 1848798721280573440 |
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| author | 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. |
| author_facet | 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. |
| author_sort | Jevnikar, Zala |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:24:16Z |
| format | Article |
| id | nottingham-52416 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:24:16Z |
| publishDate | 2018 |
| publisher | Elsevier |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-524162020-05-04T19:40:09Z https://eprints.nottingham.ac.uk/52416/ 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. 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. Elsevier 2018-06-11 Article PeerReviewed 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 and Olsson, Henric K. (2018) Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. Journal of Allergy and Clinical Immunology . ISSN 0091-6749 Asthma lung epithelium transcriptomics hierarchical clustering IL-6 signaling exacerbation frequency eosinophils airway inflammation remodeling epithelial integrity https://www.jacionline.org/article/S0091-6749(18)30847-9/abstract doi:10.1016/j.jaci.2018.05.026 doi:10.1016/j.jaci.2018.05.026 |
| spellingShingle | Asthma lung epithelium transcriptomics hierarchical clustering IL-6 signaling exacerbation frequency eosinophils airway inflammation remodeling epithelial integrity 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. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation |
| title | Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation |
| title_full | Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation |
| title_fullStr | Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation |
| title_full_unstemmed | Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation |
| title_short | Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation |
| title_sort | epithelial il-6 trans-signaling defines a new asthma phenotype with increased airway inflammation |
| topic | Asthma lung epithelium transcriptomics hierarchical clustering IL-6 signaling exacerbation frequency eosinophils airway inflammation remodeling epithelial integrity |
| url | https://eprints.nottingham.ac.uk/52416/ https://eprints.nottingham.ac.uk/52416/ https://eprints.nottingham.ac.uk/52416/ |