Asthma
Asthma is a heterogeneous, chronic disease of the airways associated
with airway hyper-reactivity, bronchoconstriction, cough, wheeze and, in
the majority of cases, inflammation. The most common and well-studied
form of asthma is the allergic type affecting both children and adults.
Allergic asthma is marked by increased circulating IgE levels and/or
positive skin prick test and triggered by various allergens from pollen
and mold to animal dander in addition to airway hyperreactivity. This
allergen trigger leads to a cascading type 2 immune response in which
type 2 cytokine production, eosinophil numbers and IgE levels are all
increased. Given the vast heterogeneity of asthma sub-phenotypes, this
section will focus primarily on findings regarding the role of miRNAs in
allergic asthma (Table 3 ).
Allergic asthma often begins in early life with up to half of adults
reporting asthma symptoms beginning in
childhood54. Thus,
several studies examined the composition of miRNAs in the circulation
and their potential as biomarkers. For example, 122 circulating miRNAs
differentiated asthmatic from non-asthmatic
children55. The
comprehensive inclusion of phenotypic characteristics in the Childhood
Asthma Management Program (CAMP) studies allowed the identification of
miRNAs that could potentially aid in the treatment of childhood
asthma56-58. These
miRNAs correlated to lung function parameters after stratification by
sex (miR-126, -139, -15b, -186, -342, -374a, -409, -660, -942, male
associated and miR-126, -1290, -142, 191, female associated) and to
bronchial hyperresponsiveness in response to methacholine challenge
(miR-296, -16 and -30d). Applying machine learning to miRNA expression
and the clinical score of asthma from the CAMP cohort, these studies
suggested a combination of miRNAs as asthma prediction markers
(miR-146b, miR-206 and
miR-720)58.
In adult asthma, a study identified a set of plasma miRNAs, miR-125b,
miR-16, miR-299-, miR-206 and miR-133b, that distinguished asthmatics
from healthy individuals and subjects with AR14.
let-7a, miR-21, -133a, -155, -328, and -1248 were all found
significantly decreased in exhaled breath condensates from asthmatic
individuals compared to healthy subjects and predicted target mRNAs
indicated numerous type 2 mediators, suggesting a role for these miRNAs
in asthma15. miR-21 has been commonly found to be
dysregulated in allergic asthma, both in the circulation and in the
airways of humans and mice8-10. miRNA expression was
also shown to be altered in a temporal manner. When allergic asthmatics
were examined in and out of the pollen season, miR-155 was found to be
downregulated in lymphocytes from induced sputum only in pollen season,
raising the question of which other miRNAs may be altered upon pollen
exposure 16. Another prevalent miRNA in asthma,
miR-19a has been shown to be a player in asthmatic airways57,59,60.
Increased expression of miR-19a in airway T cells promoted type 2
cytokine production through direct targeting of Phosphatase and Tensin
Homolog (PTEN) and A20, whereas reduced miR-19a in the airway smooth
muscle cells led to enhanced remodeling57,59.
In a recent study, decreased epithelial and sputum miR-221 were
associated with eosinophilic airway inflammation in
asthma61. Even out of
the airways, miRNAs have shown potential as predictive markers in
asthma. miRNAs from circulating eosinophils, a hallmark in asthma and
allergic disease, were examined with miR-185 distinguishing between
healthy and asthmatic subjects and showing to be a predictor of asthma
severity in blood
sera62.
Numerous biomarker studies have been conducted to find both
extracellular vesicle derived miRNAs from bronchoalveolar lavage (BAL)
and cell-specific miRNAs dysregulated in
asthma63-65. Recently
more detailed studies have identified potential miRNA targets,
suggesting that these aberrant miRNAs alter multiple signaling
processes. A negative correlation between lung function parameters and
miR-16 in asthma was recently identified. In silico analysis
predicted Adrenoreceptor B-2 (ADRB2), which is involved in bronchial
smooth muscle contraction, as a target gene for miR-16 and was later
confirmed by luciferase
assay66. Bioinformatic
analysis of miRNA targets from the blood of house dust mite allergic
asthmatic children revealed enrichment in the PI3K and NF-κB pathways.
More specifically, correlations were shown between their target miRNAs
and 3 genes: the E3 ubiquitin ligase CBL, PPARGC1B, which stimulates the
activity of various transcription factors and nuclear receptors, and the
estrogen receptor ESR1, suggesting that these pathways and genes have a
role in asthma
pathogenesis67.
Additionally, miRNA expression in asthma has been correlated to
expression and/or targeting of the type 2 cytokines59,68,
IL-13 69and
IL-570, as well as
VEGF71, key molecules
in asthma pathogenesis, strengthening the evidence for their role in the
regulation of the disease. Now that the field has a large set of
potential miRNAs that are shown to be altered in asthma, it is important
for more mechanistic studies to be performed to truly understand their
role in asthma pathogenesis.