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

Abstract

Severe asthma might be associated with overexpression of T_h17 cytokines, which induce neutrophil recruitment via neutrophil-mobilizing cytokines in airways. 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. 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. 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. 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.