Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers

• Published in: Journal of allergy and clinical immunology 2016-12, Vol.138 (6), p.1690-1700
• Main Authors: Rider, Christopher F., PhD, Yamamoto, Masatsugu, MD, Günther, Oliver P., PhD, Hirota, Jeremy A., PhD, Singh, Amrit, BS, Tebbutt, Scott J., PhD, Carlsten, Chris, MD, MPH
• Format: Article
• Language: English
• Subjects: Air pollution; Allergens - adverse effects; Allergens - immunology; Allergies; allergy; Allergy and Immunology; Asthma; Biomarkers - metabolism; controlled human exposure; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA methylation; Environmental Exposure - adverse effects; Epithelial Cells - physiology; Female; Gene expression; Gene Expression Regulation; Humans; Hypersensitivity - diagnosis; Hypersensitivity - immunology; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; Inflammation; Inflammation Mediators - metabolism; inflammatory markers; Kinases; Lung - immunology; Lung - pathology; Lungs; Male; MicroRNAs; MicroRNAs - genetics; multi-omics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathogenesis; Pathogens; Proteins; Vehicle Emissions
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.02.038

Background Air pollution's association with asthma may be due to its augmentation of allergenic effects, but the role of microRNA (miRNA) and gene expression in this synergy is unknown. Objective We sought to determine whether exposure to allergen, exposure to diesel exhaust (DE), or coexposures modulate miRNA, gene expression, or inflammatory pathways and whether these measurements are correlated. Methods Fifteen participants with atopy completed this controlled study of 2 hours of filtered air or DE (300 μg PM2.5 /m3 ) exposure, followed by saline-controlled segmental bronchial allergen challenge. Gene and miRNA expression in bronchial brushings and lung inflammatory markers were measured 48 hours later, in study arms separated by approximately 4 weeks. Expression of miRNAs, messenger RNAs, and inflammatory markers and their interrelationships were determined using regression. Results Robust linear models indicated that DE plus saline and DE plus allergen significantly modulated the highest number of miRNAs and messenger RNAs, respectively, relative to control (filtered air plus saline). In mixed models, allergen exposure modulated ( q  ≤ 0.2) miRNAs including miR-183-5p, miR-324-5p, and miR-132-3p and genes including NFKBIZ and CDKN1A , but DE did not significantly modify this allergenic effect. Repression of CDKN1A by allergen-induced miR-132-3p may contribute to shedding of bronchial epithelial cells. Conclusions Expression of specific miRNAs and genes associated with bronchial immune responses were significantly modulated by DE or allergen. However, DE did not augment the effect of allergen at 48 hours, suggesting that adjuvancy may be transient or require higher or prolonged exposure. In silico analysis suggested a possible mechanism contributing to epithelial wall damage following allergen exposure.