IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma.

TitleIFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma.
Publication TypeJournal Article
Year of Publication2018
AuthorsBhakta 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
JournalAm J Respir Crit Care Med
Volume197
Issue3
Pagination313-324
Date Published2018 Feb 01
ISSN1535-4970
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 FEV (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.

DOI10.1164/rccm.201706-1070OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID29064281
PubMed Central IDPMC5811952
Grant ListK23 HL116657 / HL / NHLBI NIH HHS / United States
P01 HL107202 / HL / NHLBI NIH HHS / United States
P30 DK072517 / DK / NIDDK NIH HHS / United States
K23 HL123778 / HL / NHLBI NIH HHS / United States
K24 HL137013 / HL / NHLBI NIH HHS / United States
U19 AI077439 / AI / NIAID NIH HHS / United States
U01 HL126493 / HL / NHLBI NIH HHS / United States

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