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

Paolo Montuschi, Nadia Mores, Adele D'Amico, 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. SterkKian 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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

53 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)577-590
Numero di pagine14
RivistaJOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume143
DOI
Stato di pubblicazionePubblicato - 2010

Keywords

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

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