- Bhakta, Nirav R;
- Christenson, Stephanie A;
- Nerella, Srilaxmi;
- Solberg, Owen D;
- Nguyen, Christine P;
- Choy, David F;
- Jung, Kyle L;
- Garudadri, Suresh;
- Bonser, Luke R;
- Pollack, Joshua L;
- Zlock, Lorna T;
- Erle, David J;
- Langelier, Charles;
- Derisi, Joseph L;
- Arron, Joseph R;
- Fahy, John V;
- Woodruff, Prescott G
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.