IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma
Bhakta NR, Christenson SA, Nerella S, Solberg OD, Nguyen CP, Choy DF, Jung KL, Garudadri S, Bonser LR, Pollack JL, Zlock LT, Erle DJ, Langelier C, Derisi JL, Arron JR, Fahy JV, Woodruff PG

ATS Journals, 2017

Abstract: Rationale: Quantification of type 2 inflammation provided a molecular basis for heterogeneity in asthma. Non–type 2 pathways that contribute to asthma pathogenesis are not well understood. Objectives: To identify dysregulated pathways beyond type 2 inflammation. Methods: We applied RNA sequencing to airway epithelial brushings obtained from subjects with stable mild asthma not on corticosteroids (n = 19) and healthy control subjects (n = 16). Sequencing reads were mapped to human and viral genomes. In the same cohort, and in a separate group with severe asthma (n = 301), we profiled blood gene expression with microarrays. Measurements and Main Results: In airway brushings from mild asthma on inhaled corticosteroids, RNA sequencing yielded 1,379 differentially expressed genes (false discovery rate < 0.01). Pathway analysis revealed increased expression of type 2 markers, IFN-stimulated genes (ISGs), and endoplasmic reticulum (ER) stress-related genes. Airway epithelial ISG expression was not associated with type 2 inflammation in asthma or with viral transcripts but was associated with reduced lung function by FEV1 (ρ = −0.72; P = 0.0004). ER stress was confirmed by an increase in XBP1 (X-box binding protein 1) splicing in mild asthma and was associated with both type 2 inflammation and ISG expression. ISGs were also the most activated genes in blood cells in asthma and were correlated with airway ISG expression (ρ = 0.55; P = 0.030). High blood ISG expression in severe asthma was similarly unrelated to type 2 inflammation. Conclusions: ISG activation is prominent in asthma, independent of viral transcripts, orthogonal to type 2 inflammation, and associated with distinct clinical features. ER stress is associated with both type 2 inflammation and ISG expression.