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

Autor: 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, Dominick E. Shaw, Norbert Krug, Jens M. Hohlfeld, Thomas Sandström, Ratko Djukanovic, Anna James, Timothy S.C. Hinks, Peter H. Howarth, Outi Vaarala, Marleen van Geest, Henric Olsson, I.M. Adcock, H. Ahmed, C. Auffray, P. Bakke, A.T. Bansal, F. Baribaud, S. Bates, E.H. Bel, J. Bigler, H. Bisgaard, M.J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, M. Caruso, A. Chaiboonchoe, P. Chanez, F.K. Chung, C.H. Compton, J. Corfield, A. D'Amico, S.E. Dahlen, B. De Meulder, R. Djukanovic, V.J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L.J. Fleming, E. Formaggio, S.J. Fowler, U. Frey, M. Gahlemann, T. Geiser, V. Goss, Y. Guo, S. Hashimoto, J. Haughney, G. Hedlin, P.W. Hekking, T. Higenbottam, J.M. Hohlfeld, C. Holweg, I. Horváth, A.J. James, R. Knowles, A.J. Knox, N. Krug, D. Lefaudeux, M.J. Loza, A. Manta, J.G. Matthews, A. Mazein, A. Meiser, R.J.M. Middelveld, M. Miralpeix, P. Montuschi, N. Mores, C.S. Murray, J. Musial, D. Myles, L. Pahus, I. Pandis, S. Pavlidis, A. Postle, P. Powel, G. Praticò, N. Rao, J. Riley, A. Roberts, G. Roberts, A. Rowe, T. Sandström, J.P.R. Schofield, W. Seibold, A. Selby, D.E. Shaw, R. Sigmund, F. Singer, P.J. Skipp, A.R. Sousa, P.J. Sterk, K. Sun, B. Thornton, W.M. van Aalderen, M. van Geest, J. Vestbo, N.H. Vissing, A.H. Wagener, S.S. Wagers, Z. Weiszhart, C.E. Wheelock, S.J. Wilson
Přispěvatelé: Publica, HUS Children and Adolescents, Commission of the European Communities, Pulmonology, AII - Inflammatory diseases, Paediatric Pulmonology
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
MMP3
Allergy
MATRIX METALLOPROTEINASES
Respiratory Medicine and Allergy
Eepithelial integrity
airway inflammation
Systemic inflammation
DISEASE
Cohort Studies
transcriptomics
0302 clinical medicine
Receptors
Immunology and Allergy
Lung
Macrophage inflammatory protein
Cells
Cultured
Lungmedicin och allergi
remodeling
Toll-like receptor
Cultured
CHITINASE-LIKE PROTEIN
3. Good health
Phenotype
TARGET
medicine.anatomical_structure
1107 Immunology
Airway Remodeling
eosinophils
medicine.symptom
Life Sciences & Biomedicine
hierarchical clustering
Signal Transduction
Adult
Settore BIO/14 - FARMACOLOGIA
Immunology
lung epithelium
03 medical and health sciences
HYPERRESPONSIVENESS
Respiratory Hypersensitivity
medicine
Humans
Hierarchical Clustering
Inflammation
Science & Technology
Innate immune system
exacerbation frequency
Interleukin-6
business.industry
Sputum
Epithelial Cells
Gene signature
Receptors
Interleukin-6
DYSFUNCTION
Asthma
respiratory tract diseases
Eosinophils
Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes study group
Cross-Sectional Studies
SEVERITY
030104 developmental biology
Gene Expression Regulation
030228 respiratory system
INTERLEUKIN-6 RECEPTOR
BARRIER FUNCTION
3121 General medicine
internal medicine and other clinical medicine
CELLS
epithelial integrity
IL-6 signaling
Exacerbation frequency
Transcriptome
business
Biomarkers
Zdroj: 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; ... (2019). Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. Journal of allergy and clinical immunology, 143(2), pp. 577-590. Elsevier 10.1016/j.jaci.2018.05.026
Journal of allergy and clinical immunology, 143(2), 577-590. Mosby Inc.
Jevnikar, Z, Östling, J, Ax, E, Calvén, J, Thörn, K, Israelsson, E, Öberg, L, Singhania, A, Lau, L C K, Wilson, S J, Ward, J A, Chauhan, A, Sousa, A R, De Meulder, B, Loza, M J, Baribaud, F, Sterk, P J, Chung, K F, Sun, K, Guo, Y, Adcock, I M, Payne, D, Dahlen, B, Chanez, P, Shaw, D E, Krug, N, Hohlfeld, J M, Sandström, T, Djukanovic, R, James, A, Hinks, T S C, Howarth, P H, Vaarala, O, Van Geest, M, Olsson, H, Adcock, I M, Ahmed, H, Auffray, C, Bakke, P, Bansal, A T, Baribaud, F, Bates, S, Bel, E H, Bigler, J, Bisgaard, H, Boedigheimer, M J, Bønnelykke, K, Brandsma, J, Brinkman, P, Bucchioni, E, Burg, D, Bush, A, Caruso, M, Chaiboonchoe, A, Chanez, P, Chung, F K, Compton, C H, Corfield, J, D'amico, A, Dahlen, S E, De Meulder, B, Djukanovic, R, Erpenbeck, V J, Erzen, D, Fichtner, K, Fitch, N, Fleming, L J, Formaggio, E, Fowler, S J, Frey, U, Gahlemann, M, Geiser, T, Goss, V, Guo, Y, Hashimoto, S, Haughney, J, Hedlin, G, Hekking, P W, Higenbottam, T, Hohlfeld, J M, Holweg, C, Horváth, I, James, A J, Knowles, R, Knox, A J, Krug, N, Lefaudeux, D, Loza, M J, Manta, A, Matthews, J G, Mazein, A, Meiser, A, Middelveld, R J M, Miralpeix, M, Montuschi, P, Mores, N, Murray, C S, Musial, J, Myles, D, Pahus, L, Pandis, I, Pavlidis, S, Postle, A, Powel, P, Praticò, G, Rao, N, Riley, J, Roberts, A, Roberts, G, Rowe, A, Sandström, T, Schofield, J P R, Seibold, W, Selby, A, Shaw, D E, Sigmund, R, Singer, F, Skipp, P J, Sousa, A R, Sterk, P J, Sun, K, Thornton, B, Van Aalderen, W M, Van Geest, M, Vestbo, J, Vissing, N H, Wagener, A H, Wagers, S S, Weiszhart, Z, Wheelock, C E & Wilson, S J 2018, ' 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
ISSN: 0091-6749
DOI: 10.1016/j.jaci.2018.05.026
Popis: BackgroundAlthough 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.ObjectiveWe sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.MethodsAn 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.ResultsActivation 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.ConclusionsLocal 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.
Databáze: OpenAIRE
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