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.