Identification of Bronchial Epithelial Genes Associated with Type-2 Eosinophilic Inflammation in Asthma.

Abstract

Background: Airway inflammation has a critical role in asthma pathogenesis and pathophysiology. Yet, the molecular pathways contributing to airway inflammation are not fully known, particularly Type-2 (T2) inflammation characterized by both eosinophilia and higher FeNO levels.

Objective: To identify genes whose level of expression in epithelial brushing samples were associated with both bronchoalveolar lavage (BAL) eosinophilia and generation of FeNO.

Methods: We performed segmental allergen bronchoprovocation (SBP-Ag) in participants with asthma, and RNA-sequencing (RNA-seq) analyses of BAL cells and brushing samples before and 48 h after SBP-Ag to identify regulation of eosinophil recruitment and FeNO changes.

Results: Allergen bronchoprovocation increased FeNO levels, which correlated with eosinophilia. Thirteen genes were identified in brushing samples, whose expression changed in response to SBP-Ag and correlated with both airway eosinophilia and FeNO levels after SBP-Ag. Among these 13 genes, the epithelial cell product, CDH26/cadherin-26 contributed to the amplification of T2 inflammation, as reflected by eosinophilia and FeNO, and causal mediation analyses with pro-T2 and pro-eosinophilic cytokine mediators in BAL fluids. Among the genes associated with reduced eosinophilia and FeNO, HEY2 is known to enhance cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT), as well as to reduce apoptosis.

Conclusion: This unbiased RNA-seq analysis in participants with allergic asthma revealed several epithelial cell genes, particularly CDH26, that may be critical for the development or augmentation of T2 inflammation in asthma.