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

BACKGROUND: Severe asthma might be associated with neutrophil recruitment and Th17 cytokines over-expression in bronchial biopsies.

OBJECTIVE: To study IL-17-related cytokines in nasal/bronchial biopsies from controls and mild (MA)-to-severe (SA) asthmatics 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 (IHC) in cryostat sections of bronchial/nasal biopsies obtained from 33 SA (21 frequent exacerbators (FE)), 31 MA (3 FE) and 14 controls. IL-17F protein was also measured by ELISA in bronchial/nasal lysates and by IHC in bronchial tissue obtained from subjects died for fatal asthma. Immunofluorescence/confocal microscopy was used for IL-17F co-localization.

RESULTS: Higher number (p<0.05) of neutrophils, IL-17A(+), IL-17F(+) and IL-21(+) cells in bronchial biopsies and higher number (p<0.01) of IL-17F(+) and IL-21(+) cells in nasal biopsies were observed in SA compared to MA. 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). FE showed increased number of bronchial neutrophils/eosinophils/CD4(+)/CD8(+) cells and bronchial/nasal IL-17F(+) cells. ROC curve analysis evidenced predictive cut-off values of bronchial neutrophils and nasal/bronchial IL-17F for discriminating between asthmatics and controls, between MA and SA and between FE and non-FE. IL-17F protein increased in bronchial/nasal lysates of SA and FE and in bronchial tissue of fatal asthma. IL-17F co-localized 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 frequent exacerbators.