The role of air pollution in miRNA regulation
In addition to viral infections, air pollution and cigarette smoke exposure are important contributors to asthma development and/or exacerbations81-89. Air pollution is not only associated with aggravated type 2 responses, but can also lead to elevated neutrophil levels which are also a source of miRNAs 90. Since exposure to air pollution alters miRNA expression both in the lungs and in blood (reviewed in91), this could represent an important immunomodulatory mechanism in asthma. However, studies that investigate miRNA expression and function in association with air pollution and allergy or asthma are scarce (Table 5).In bronchial brushings from atopic individuals exposed to diesel exhaust and allergen, miR-183, -324 and -132- expression was modulated by allergen exposure, but not by diesel exhaust92. Diesel exhaust exposure on the other hand increased expression of miR-21, -30e, -215 and -144 in blood of mild asthmatics. Importantly, miR-21 and miR-144 expression was associated with increased oxidative stress markers and reduced antioxidant gene expression93. In Chinese children, increased miR-155 in the serum of asthmatic children correlated with particulate matter level exposure94. Indirect exposure by maternal smoking reduced miR-199a expression in cord blood. Interestingly, miR-199a targets the receptor tyrosine kinase AXL, which is more methylated upon maternal smoking and the combination of maternal smoking and AXL methylation modifies the risk of childhood bronchitis symptoms95. Tobacco smoke exposure is also associated with increased miR-223 expression in maternal and cord blood and with low numbers of regulatory T cells, which could be important in asthma development96. This miRNA was also identified in induced sputum of patients with severe asthma (both atopic and non-atopic) and was associated with increased neutrophils97. In lung tissue of murine models with in utero smoke exposure combined with allergen challenge, the expression of miR-221, -16, -155, -21- and -18a was increased, whereas miR-130a expression was reduced compared to lungs challenged with allergen only98,99. Similarly, 133 microRNAs were dysregulated in fetal murine lungs upon maternal smoking. Bioinformatic network analyses that included microRNAs and transcriptional regulators revealed insulin-like growth factor (Igf-1) as major hub. Dysregulation of IgF-1 was confirmed in PBMCs of healthy school-aged children with early-life smoke exposure100. Expression analysis and functional experiments in epithelial cells (primary and cell lines) exposed to air pollution have revealed miRNA involvement in several processes that can be important in asthma, such as oxidative stress, apoptosis, autophagy, NF-κB signaling and epithelial to mesenchymal transition (Figure 2 )101-113. miRNAs reported to be involved in chronic obstructive pulmonary disease (reviewed in 114-116) may also be important in asthma aggravated by air pollution. Although the actual involvement of these miRNAs in asthma remains to be further investigated, they could become interesting tools for exposure and risk assessment.