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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Jevnikar, Zala¹  Ostling, Jorgen¹  Calven, Jenny^1,2  Thorn, Kristofer¹  Israelsson, Elisabeth¹  Oberg, Lisa¹  Singhania, Akul³  Lau, Laurie C. K.³  Wilson, Susan J.^3,5  Ward, Jonathan A.^3,5  Chauhan, Anoop⁶  Sousa, Ana R.⁷  De Meulder, Bertrand⁸  Loza, Matthew J.⁹  Baribaud, Frederic⁹  Sterk, Peter J.¹⁰  Chung, Kian Fan^11,12,13  Sun, Kai¹⁴  Guo, Yike¹⁴  Adcock, Ian M.^11,12,13  Payne, Debbie¹⁵  Dahlen, Barbro^16,17  Chanez, Pascal¹⁹  Shaw, Dominick E.²⁰  Krug, Norbert^21,22  Hohlfeld, Jens M.^21,22,23  Sandstrom, Thomas²⁴  Djukanovic, Ratko⁴  James, Anna¹⁸  Hinks, Timothy S. C.^3,4,25  Howarth, Peter H.^3,4  Vaarala, Outi¹  van Geest, Marleen¹  Olsson, Henric¹ 

[1] AstraZeneca, IMED Biotech Unit, Dept Biosci Resp Inflammat & Autoimmun, Gothenburg, Sweden

[2] Univ Gothenburg, Inst Med, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden

[3] Univ Southampton, Fac Med, Clin & Expt Sci, Southampton, Hants, England

[4] Southampton Univ Hosp, NIHR Southampton Resp Biomed Res Unit, Southampton, Hants, England

[5] Univ Southampton, Fac Med, Histochem Res Unit, Southampton, Hants, England

[6] Portsmouth Hosp NHS Trust, Portsmouth, Hants, England

[7] GlaxoSmithKline, Discovery Med, Brentford, England

[8] Univ Lyon, CNRS ENS UCBL INSERM, CIRI UMR5308, European Inst Syst Biol & Med, Lyon, France

[9] Johnson & Johnson, Janssen R&D, Spring House, PA USA

[10] Acad Med Ctr, Dept Resp Med, Amsterdam, Netherlands

[11] Imperial Coll London, Natl Heart & Lung Inst, London, England

[12] Royal Brompton & Harefield NHS Fdn Trust, Royal Brompton Biomed Res Unit, London, England

[13] Imperial Coll London, London, England

[14] Imperial Coll London, Dept Comp & Data Sci Inst, London, England

[15] Univ Manchester, Ctr Integrated Genom Med Res, Manchester, Lancs, England

[16] Karolinska Univ Hosp, Stockholm, Sweden

[17] Ctr Allergy Res, Stockholm, Sweden

[18] Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res, Stockholm, Sweden

[19] Univ Mediterranee, Marseille, France

[20] Univ Nottingham, Resp Biomed Res Unit, Nottingham, England

[21] Fraunhofer Inst Toxicol & Expt Med, Hannover, Germany

[22] German Ctr Lung Res, Hannover, Germany

[23] Hannover Med Sch, Dept Resp Med, Hannover, Germany

[24] Umea Univ, Dept Publ Hlth & Clin Med, Med, Umea, Sweden

[25] Univ Oxford, NDM Expt Med, Resp Med Unit, John Radcliffe Hosp, Oxford, England

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

DOI  :  10.1016/j.jaci.2018.05.026

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free