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

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; Adele 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; 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; Paolo Montuschi; Nadia 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

doi:10.1016/j.jaci.2018.05.026

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

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 GuoIan 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, Adele 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, 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, Paolo Montuschi, Nadia 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

Research output: Contribution to journal › Article

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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.

Original language	English
Pages (from-to)	577-590
Number of pages	14
Journal	Journal of Allergy and Clinical Immunology
Volume	143
DOIs	https://doi.org/10.1016/j.jaci.2018.05.026
Publication status	Published - 2010

Keywords

Adult
Airway Remodeling
Asthma
Biomarkers
Cells, Cultured
Cohort Studies
Cross-Sectional Studies
Epithelial Cells
Gene Expression Regulation
Humans
IL-6 signaling
Inflammation
Interleukin-6
Lung
Male
Phenotype
Receptors, Interleukin-6
Respiratory Hypersensitivity
Signal Transduction
Sputum
Transcriptome
airway inflammation
eosinophils
epithelial integrity
exacerbation frequency
hierarchical clustering
lung epithelium
remodeling
transcriptomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaci.2018.05.026

Cite this

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., ... Wilson, S. J. (2010). Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. Journal of Allergy and Clinical Immunology, 143, 577-590. https://doi.org/10.1016/j.jaci.2018.05.026

@article{84b6f582a6cd44fcbe94100024ae4203,

title = "Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation",

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.",

keywords = "Adult, Airway Remodeling, Asthma, Biomarkers, Cells, Cultured, Cohort Studies, Cross-Sectional Studies, Epithelial Cells, Gene Expression Regulation, Humans, IL-6 signaling, Inflammation, Interleukin-6, Lung, Male, Phenotype, Receptors, Interleukin-6, Respiratory Hypersensitivity, Signal Transduction, Sputum, Transcriptome, airway inflammation, eosinophils, epithelial integrity, exacerbation frequency, hierarchical clustering, lung epithelium, remodeling, transcriptomics, Adult, Airway Remodeling, Asthma, Biomarkers, Cells, Cultured, Cohort Studies, Cross-Sectional Studies, Epithelial Cells, Gene Expression Regulation, Humans, IL-6 signaling, Inflammation, Interleukin-6, Lung, Male, Phenotype, Receptors, Interleukin-6, Respiratory Hypersensitivity, Signal Transduction, Sputum, Transcriptome, airway inflammation, eosinophils, epithelial integrity, exacerbation frequency, hierarchical clustering, lung epithelium, remodeling, transcriptomics",

author = "Zala Jevnikar and J{\"o}rgen {\"O}stling and Elisabeth Ax and Jenny Calv{\'e}n and Kristofer Th{\"o}rn and Elisabeth Israelsson and Lisa {\"O}berg and Akul Singhania and Lau, {Laurie C.K.} and Wilson, {Susan J.} and Ward, {Jonathan A.} and Anoop Chauhan and Sousa, {Ana R.} and {De Meulder}, Bertrand and Loza, {Matthew J.} and Fr{\'e}d{\'e}ric Baribaud and Sterk, {Peter J.} and Chung, {Kian Fan} and Kai Sun and Yike Guo and Adcock, {Ian M.} and Debbie Payne and Barbro Dahlen and Pascal Chanez and Shaw, {Dominick E.} and Norbert Krug and Hohlfeld, {Jens M.} and Thomas Sandstr{\"o}m and Ratko Djukanovic and Anna James and Hinks, {Timothy S.C.} and Howarth, {Peter H.} and Outi Vaarala and {Van Geest}, Marleen and Henric Olsson and Adcock, {I. M.} and H. Ahmed and C. Auffray and P. Bakke and Bansal, {A. T.} and F. Baribaud and S. Bates and Bel, {E. H.} and J. Bigler and H. Bisgaard and Boedigheimer, {M. J.} and K. B{\o}nnelykke and J. Brandsma and P. Brinkman and E. Bucchioni and D. Burg and A. Bush and M. Caruso and A. Chaiboonchoe and P. Chanez and Chung, {F. K.} and Compton, {C. H.} and J. Corfield and A. D'Amico and Adele D'Amico and Dahlen, {S. E.} and {De Meulder}, B. and R. Djukanovic and Erpenbeck, {V. J.} and D. Erzen and K. Fichtner and N. Fitch and Fleming, {L. J.} and E. Formaggio and Fowler, {S. J.} and U. Frey and M. Gahlemann and T. Geiser and V. Goss and S. Hashimoto and J. Haughney and G. Hedlin and Hekking, {P. W.} and T. Higenbottam and Hohlfeld, {J. M.} and C. Holweg and I. Horv{\'a}th and James, {A. J.} and R. Knowles and Knox, {A. J.} and N. Krug and D. Lefaudeux and Loza, {M. J.} and A. Manta and Matthews, {J. G.} and A. Mazein and A. Meiser and Middelveld, {R. J.M.} and M. Miralpeix and Paolo Montuschi and Nadia Mores and Murray, {C. S.} and J. Musial and D. Myles and L. Pahus and I. Pandis and S. Pavlidis and A. Postle and P. Powel and G. Pratic{\`o} and N. Rao and J. Riley and A. Roberts and G. Roberts and A. Rowe and T. Sandstr{\"o}m and Schofield, {J. P.R.} and W. Seibold and A. Selby and Shaw, {D. E.} and R. Sigmund and F. Singer and Skipp, {P. J.} and Sousa, {A. R.} and Sterk, {P. J.} and K. Sun and B. Thornton and {Van Aalderen}, {W. M.} and {Van Geest}, M. and J. Vestbo and Vissing, {N. H.} and Wagener, {A. H.} and Wagers, {S. S.} and Z. Weiszhart and Wheelock, {C. E.} and Wilson, {S. J.}",

year = "2010",

doi = "10.1016/j.jaci.2018.05.026",

language = "English",

volume = "143",

pages = "577--590",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Year Book Incorporated:6277 Sea Harbor Drive:Orlando, FL 32887:(800)654-2452, (407)345-4000, EMAIL: [email protected], INTERNET: http://www.mosby.com, Fax: (407)363-9661, (314)432-1380",

}

Jevnikar, Z, Östling, J, Ax, E, Calvén, J, Thörn, K, Israelsson, E, Öberg, L, Singhania, A, Lau, LCK, Wilson, SJ, Ward, JA, Chauhan, A, Sousa, AR, De Meulder, B, Loza, MJ, Baribaud, F, Sterk, PJ, Chung, KF, Sun, K, Guo, Y, Adcock, IM, Payne, D, Dahlen, B, Chanez, P, Shaw, DE, Krug, N, Hohlfeld, JM, Sandström, T, Djukanovic, R, James, A, Hinks, TSC, Howarth, PH, Vaarala, O, Van Geest, M, Olsson, H, Adcock, IM, Ahmed, H, Auffray, C, Bakke, P, Bansal, AT, Baribaud, F, Bates, S, Bel, EH, Bigler, J, Bisgaard, H, Boedigheimer, MJ, Bønnelykke, K, Brandsma, J, Brinkman, P, Bucchioni, E, Burg, D, Bush, A, Caruso, M, Chaiboonchoe, A, Chanez, P, Chung, FK, Compton, CH, Corfield, J, D'Amico, A, D'Amico, A, Dahlen, SE, De Meulder, B, Djukanovic, R, Erpenbeck, VJ, Erzen, D, Fichtner, K, Fitch, N, Fleming, LJ, Formaggio, E, Fowler, SJ, Frey, U, Gahlemann, M, Geiser, T, Goss, V, Hashimoto, S, Haughney, J, Hedlin, G, Hekking, PW, Higenbottam, T, Hohlfeld, JM, Holweg, C, Horváth, I, James, AJ, Knowles, R, Knox, AJ, Krug, N, Lefaudeux, D, Loza, MJ, Manta, A, Matthews, JG, Mazein, A, Meiser, A, Middelveld, RJM, Miralpeix, M, Montuschi, P , Mores, N, Murray, CS, 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, JPR, Seibold, W, Selby, A, Shaw, DE, Sigmund, R, Singer, F, Skipp, PJ, Sousa, AR, Sterk, PJ, Sun, K, Thornton, B, Van Aalderen, WM, Van Geest, M, Vestbo, J, Vissing, NH, Wagener, AH, Wagers, SS, Weiszhart, Z, Wheelock, CE & Wilson, SJ 2010, 'Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation', Journal of Allergy and Clinical Immunology, vol. 143, pp. 577-590. https://doi.org/10.1016/j.jaci.2018.05.026

TY - JOUR

T1 - Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

AU - Jevnikar, Zala

AU - Östling, Jörgen

AU - Ax, Elisabeth

AU - Calvén, Jenny

AU - Thörn, Kristofer

AU - Israelsson, Elisabeth

AU - Öberg, Lisa

AU - Singhania, Akul

AU - Lau, Laurie C.K.

AU - Wilson, Susan J.

AU - Ward, Jonathan A.

AU - Chauhan, Anoop

AU - Sousa, Ana R.

AU - De Meulder, Bertrand

AU - Loza, Matthew J.

AU - Baribaud, Frédéric

AU - Sterk, Peter J.

AU - Chung, Kian Fan

AU - Sun, Kai

AU - Guo, Yike

AU - Adcock, Ian M.

AU - Payne, Debbie

AU - Dahlen, Barbro

AU - Chanez, Pascal

AU - Shaw, Dominick E.

AU - Krug, Norbert

AU - Hohlfeld, Jens M.

AU - Sandström, Thomas

AU - Djukanovic, Ratko

AU - James, Anna

AU - Hinks, Timothy S.C.

AU - Howarth, Peter H.

AU - Vaarala, Outi

AU - Van Geest, Marleen

AU - Olsson, Henric

AU - Adcock, I. M.

AU - Ahmed, H.

AU - Auffray, C.

AU - Bakke, P.

AU - Bansal, A. T.

AU - Baribaud, F.

AU - Bates, S.

AU - Bel, E. H.

AU - Bigler, J.

AU - Bisgaard, H.

AU - Boedigheimer, M. J.

AU - Bønnelykke, K.

AU - Brandsma, J.

AU - Brinkman, P.

AU - Bucchioni, E.

AU - Burg, D.

AU - Bush, A.

AU - Caruso, M.

AU - Chaiboonchoe, A.

AU - Chanez, P.

AU - Chung, F. K.

AU - Compton, C. H.

AU - Corfield, J.

AU - D'Amico, A.

AU - D'Amico, Adele

AU - Dahlen, S. E.

AU - De Meulder, B.

AU - Djukanovic, R.

AU - Erpenbeck, V. J.

AU - Erzen, D.

AU - Fichtner, K.

AU - Fitch, N.

AU - Fleming, L. J.

AU - Formaggio, E.

AU - Fowler, S. J.

AU - Frey, U.

AU - Gahlemann, M.

AU - Geiser, T.

AU - Goss, V.

AU - Hashimoto, S.

AU - Haughney, J.

AU - Hedlin, G.

AU - Hekking, P. W.

AU - Higenbottam, T.

AU - Hohlfeld, J. M.

AU - Holweg, C.

AU - Horváth, I.

AU - James, A. J.

AU - Knowles, R.

AU - Knox, A. J.

AU - Krug, N.

AU - Lefaudeux, D.

AU - Loza, M. J.

AU - Manta, A.

AU - Matthews, J. G.

AU - Mazein, A.

AU - Meiser, A.

AU - Middelveld, R. J.M.

AU - Miralpeix, M.

AU - Montuschi, Paolo

AU - Mores, Nadia

AU - Murray, C. S.

AU - Musial, J.

AU - Myles, D.

AU - Pahus, L.

AU - Pandis, I.

AU - Pavlidis, S.

AU - Postle, A.

AU - Powel, P.

AU - Praticò, G.

AU - Rao, N.

AU - Riley, J.

AU - Roberts, A.

AU - Roberts, G.

AU - Rowe, A.

AU - Sandström, T.

AU - Schofield, J. P.R.

AU - Seibold, W.

AU - Selby, A.

AU - Shaw, D. E.

AU - Sigmund, R.

AU - Singer, F.

AU - Skipp, P. J.

AU - Sousa, A. R.

AU - Sterk, P. J.

AU - Sun, K.

AU - Thornton, B.

AU - Van Aalderen, W. M.

AU - Van Geest, M.

AU - Vestbo, J.

AU - Vissing, N. H.

AU - Wagener, A. H.

AU - Wagers, S. S.

AU - Weiszhart, Z.

AU - Wheelock, C. E.

AU - Wilson, S. J.

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

KW - Adult

KW - Airway Remodeling

KW - Asthma

KW - Biomarkers

KW - Cells, Cultured

KW - Cohort Studies

KW - Cross-Sectional Studies

KW - Epithelial Cells

KW - Gene Expression Regulation

KW - Humans

KW - IL-6 signaling

KW - Inflammation

KW - Interleukin-6

KW - Lung

KW - Male

KW - Phenotype

KW - Receptors, Interleukin-6

KW - Respiratory Hypersensitivity

KW - Signal Transduction

KW - Sputum

KW - Transcriptome

KW - airway inflammation

KW - eosinophils

KW - epithelial integrity

KW - exacerbation frequency

KW - hierarchical clustering

KW - lung epithelium

KW - remodeling

KW - transcriptomics

KW - Adult

KW - Airway Remodeling

KW - Asthma

KW - Biomarkers

KW - Cells, Cultured

KW - Cohort Studies

KW - Cross-Sectional Studies

KW - Epithelial Cells

KW - Gene Expression Regulation

KW - Humans

KW - IL-6 signaling

KW - Inflammation

KW - Interleukin-6

KW - Lung

KW - Male

KW - Phenotype

KW - Receptors, Interleukin-6

KW - Respiratory Hypersensitivity

KW - Signal Transduction

KW - Sputum

KW - Transcriptome

KW - airway inflammation

KW - eosinophils

KW - epithelial integrity

KW - exacerbation frequency

KW - hierarchical clustering

KW - lung epithelium

KW - remodeling

KW - transcriptomics

UR - http://hdl.handle.net/10807/170029

U2 - 10.1016/j.jaci.2018.05.026

DO - 10.1016/j.jaci.2018.05.026

M3 - Article

SN - 0091-6749

VL - 143

SP - 577

EP - 590

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

ER -

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

Abstract

Keywords

UN SDGs

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