Identification of IL-17F/frequent exacerbator endotype in asthma

Fabio L M Ricciardolo, Valentina Sorbello, Anna Folino, Fabio Gallo, Gian Mario Massaglia, Gabriella Favatà, Salvatore Conticello, Davide Vallese, Federica Gani, Mario Malerba, Gert Folkerts, Giovanni Rolla, Mirella Profita, Thais Mauad, Antonino Di Stefano, Giorgio Ciprandi

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Abstract

BACKGROUND: Severe asthma might be associated with overexpression of Th17 cytokines, which induce neutrophil recruitment via neutrophil-mobilizing cytokines in airways.

OBJECTIVE: To study IL-17-related cytokines in nasal/bronchial biopsies from controls and mild asthmatics (MAs) to severe asthmatics (SAs) in relation to exacerbation rate.

METHODS: Inflammatory cells and IL-17A(+), IL-17F(+), IL-21(+), IL-22(+), and IL-23(+) cells were examined by immunohistochemistry in cryostat sections of bronchial/nasal biopsies obtained from 33 SAs (21 frequent exacerbators [FEs]), 31 MAs (3 FEs), and 14 controls. IL-17F protein was also measured by ELISA in bronchial/nasal lysates and by immunohistochemistry in bronchial tissue obtained from subjects who died because of fatal asthma. Immunofluorescence/confocal microscopy was used for IL-17F colocalization.

RESULTS: Higher number (P < .05) of neutrophils, IL-17A(+), IL-17F(+), and IL-21(+) cells in bronchial biopsies and higher numbers (P < .01) of IL-17F(+) and IL-21(+) cells in nasal biopsies were observed in SAs compared with MAs. Bronchial IL-17F(+) cells correlated with bronchial neutrophils (r = 0.54), exacerbation rate (r = 0.41), and FEV1 (r = -0.46). Nasal IL-17F(+) cells correlated with bronchial IL-17F (r = 0.35), exacerbation rate (r = 0.47), and FEV1 (r = -0.61). FEs showed increased number of bronchial neutrophils/eosinophils/CD4(+)/CD8(+) cells and bronchial/nasal IL-17F(+) cells. Receiver operating characteristic curve analysis evidenced predictive cutoff values of bronchial neutrophils and nasal/bronchial IL-17F for discriminating between asthmatics and controls, between MAs and SAs and between FEs and non-FEs. IL-17F protein increased in bronchial/nasal lysates of SAs and FEs and in bronchial tissue of fatal asthma. IL-17F colocalized in CD4(+)/CD8(+) cells.

CONCLUSIONS: IL-17-related cytokines expression was amplified in bronchial/nasal mucosa of neutrophilic asthma prone to exacerbation, suggesting a pathogenic role of IL-17F in FEs.

Original languageEnglish
Pages (from-to)395-406
Number of pages12
JournalJournal of Allergy and Clinical Immunology
Volume140
Issue number2
DOIs
Publication statusPublished - Aug 2017

Keywords

  • Journal Article

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    Ricciardolo, F. L. M., Sorbello, V., Folino, A., Gallo, F., Massaglia, G. M., Favatà, G., Conticello, S., Vallese, D., Gani, F., Malerba, M., Folkerts, G., Rolla, G., Profita, M., Mauad, T., Di Stefano, A., & Ciprandi, G. (2017). Identification of IL-17F/frequent exacerbator endotype in asthma. Journal of Allergy and Clinical Immunology, 140(2), 395-406. https://doi.org/10.1016/j.jaci.2016.10.034