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\begin{document}

\title{Spotlight on microRNAs in allergy and asthma}



\author[1]{Julie Weidner}%
\author[2]{Sabine Bartel}%
\author[3]{Ayse Kilic}%
\author[4]{Ulrich Zissler}%
\author[5]{Harald Renz}%
\author[6]{Jürgen Schwarze}%
\author[7]{Carsten Schmidt-Weber}%
\author[8]{Tania Maes}%
\author[9]{Ana Rebane}%
\author[10]{Susanne Krauss-Etschmann}%
\author[11]{Madeleine Rådinger}%
\affil[1]{University of Gothenburg, Institute of Medicine}%
\affil[2]{Universitair Medisch Centrum Groningen}%
\affil[3]{Brigham and Women’s Hospital}%
\affil[4]{ZAUM – Center for Allergy and Environment }%
\affil[5]{Philipps University}%
\affil[6]{University of Edinburgh, Edinburgh}%
\affil[7]{ZAUM – Center for Allergy and Environment}%
\affil[8]{Ghent University}%
\affil[9]{University of Tartu}%
\affil[10]{Forschungszentrum Borstel Leibniz-Zentrum fur Medizin und Biowissenschaften}%
\affil[11]{University of Gothenburg}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
In past ten years, microRNAs (miRNAs) have gained scientific attention
due to their importance in the pathophysiology of allergic diseases and
their potential as biomarkers in liquid biopsies. They act as master
post-transcriptional regulators that control most cellular processes. As
one miRNA can target several mRNAs, often within the same pathway,
dysregulated expression of miRNAs may alter particular cellular
responses and contribute or lead to the development of various diseases.
In this review, we give an overview of the current research on miRNAs in
allergic diseases, including atopic dermatitis, allergic rhinitis and
asthma. Specifically, we discuss how individual miRNAs function in the
regulation of immune responses in epithelial cells and specialized
immune cells in response to different environmental factors and
respiratory viruses. In addition, we review insights obtained from
experiments with murine models of allergic airway and skin inflammation
and offer an overview of studies focusing on miRNA discovery using
profiling techniques and bioinformatic modelling of the network effect
of multiple miRNAs. In conclusion, we highlight the importance of
research into miRNA function in allergy and asthma to improve our
knowledge of the molecular mechanisms involved in the pathogenesis of
this heterogeneous group of diseases.%
\end{abstract}%



\sloppy




\textbf{Introduction}

The human body is constantly subjected to an onslaught of allergens and
environmental irritants. These particles can trigger immune and
inflammatory responses leading to a variety of alterations in gene
expression. In recent years, the study of non-coding RNAs has led to an
increased understanding that gene regulation is more complex than
previously imagined\textsuperscript{1,2}. Among other mechanisms, small
non-coding microRNAs (miRNAs) have found themselves in the role of
central regulators of gene expression at the post-transcriptional level.
The details of miRNA molecular function, biogenesis and processing have
been thoroughly described in several reviews\textsuperscript{1-4}. In
canonical miRNA processing, miRNAs are transcribed by RNA polymerase II
as a pri-miRNA which is then processed by the enzymes DROSHA and DCGR8
in the nucleus to form a pre-miRNA. This pre-miRNA hairpin is exported
to the cytoplasm where is it cleaved by DICER into a miRNA duplex. One
of the two strands is loaded into AGO2, whereas the other is degraded.
It should be highlighted that miRNAs often initiate the downregulation
of their target genes via imperfect binding to the 3' untranslated
regions of mRNAs. This imperfect binding leads to the suppression of
multiple targets by one miRNA, while a single mRNA can be influenced by
several miRNAs. There are several points to take into account when
understanding miRNA nomenclature\textsuperscript{5}. 1.) Novel miRNAs
are named sequentially although there are exceptions for ``historical''
miRNAs such as let-7 and lin-4 which were first discovered in \emph{C.
elegans} . Currently, over 2500 miRNAs have been verified. 2.) miRNA
clusters are areas where two or more miRNAs are transcribed from
adjacent miRNA genes (e.g. miR17\textasciitilde{}92). 3.) miRNA strands
are named -5p or -3p indicating if they originate from the 5' or 3' arm
and either may be responsible for regulating cellular processes.
Nowadays technological advances such as real-time PCR, microarray and
next generation sequencing have greatly simplified the identification
and validation of miRNAs, allowing for the exponential growth of
investigation of miRNAs as regulatory molecules in a wide variety of
research areas.

Although miRNAs were first discovered nearly thirty years ago, their
detailed role in the immune system has only begun to be elucidated in
the past decade. While more thoroughly studied in cancer, recent
research has reported miRNA expression to be altered in skin conditions
and a variety of lung diseases, including, but not limited to:
idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive
pulmonary disease, and asthma\textsuperscript{6-10}. The use of model
systems, such as cell culture and mouse models, have furthered our
knowledge of the mechanistic role of miRNAs in airway hyper-reactivity,
allergy and immune responses\textsuperscript{2,4,11-13}. Research into
the role of miRNAs in allergy is expanding and many potential players
have been identified in mouse models or \emph{in vitro} studies, but
their real role in human disease still remains poorly understood.

This review highlights the recent steps towards a better understanding
of the role of miRNAs in allergic diseases including atopic dermatitis
(AD), allergic rhinitis (AR) and asthma. Currently, sufficient evidence
exists for miRNA regulation in the pathogeneses of these three allergic
diseases, but, there is increasing evidence for a role of miRNAs in
other allergic diseases such as food allergy or chronic
rhinosinusitis\textsuperscript{4,10,13-29}.\textbf{Figure 1} provides an
overview of miRNAs in cells and tissues that are associated with
allergic diseases.

\textbf{Human Disease}

\textbf{Atopic dermatitis}

AD is a complex chronic inflammatory skin disease that is associated
with skin barrier defects and the activation of immune responses in the
skin by environmental allergens and/or intrinsic
factors.\textsuperscript{30} Although type 2 inflammatory responses and
elevated IgE are known as the main characteristics of AD, some patients
actually develop stronger T helper cell (Th) Th17/Th22
responses\textsuperscript{31}. Among other characteristic features,
activation of keratinocytes with some similarities to another
inflammatory skin disease, psoriasis, plays an important role in
AD\textsuperscript{30,32}. Research on miRNAs in AD started with an
array analysis of lesional skin samples from AD and psoriasis patients.
The results of this early study suggested that alterations in miRNA
levels in the skin of AD patients partially overlapped with that of
psoriatic skin and include multiple miRNAs shown to be modulated in
other inflammatory conditions\textsuperscript{33}. For example, miR-21
and miR-146a were shown to be upregulated in the skin of psoriasis and
AD patients\textsuperscript{33}, of which miR-21 function in airway
inflammation is discussed in other sections of this review. miR-146a was
demonstrated to inhibit many pro-inflammatory chemokines in
keratinocytes through targeting multiple factors of the NF\selectlanguage{greek}κ-\selectlanguage{english}B
pathway\textsuperscript{34-37} and miR-146a-deficient mice developed
stronger inflammation in both AD and psoriasis
models\textsuperscript{36,38}. On the other hand, it has been shown that
miR-146a deficiency in mice leads to a defect in IgE
production\textsuperscript{39,40}and is linked to a type 1/type 17
skewing phenotype\textsuperscript{41}. However, as a negative
relationship between miR-146a and IgE levels in patient serum samples
was detected\textsuperscript{39}. It appears that miR-146a is needed for
the production of IgE and suppression of type 1/17-cell-mediated immune
responses in mice. Therefore, the increased expression of miR-146a in
the case of allergic inflammation might have limited influence on type-2
cell-mediated immune responses in a subgroup of AD patients with
increased IgE.

Another miRNA that may influence the development of AD through its
function in the immune system is miR-155. It was shown that miR-155 is
overexpressed in the skin of AD patients, most likely due to
infiltrating immune cells, and suggested that miR-155 may influence the
development of AD through the downregulation of cytotoxic T
lymphocyte-associated antigen 4 (CTLA4), a negative regulator of T cell
activation\textsuperscript{37}. In addition, it was reported that
miR-155~expression positively correlated with AD severity, the number of
Th17 cells and IL-17 mRNA expression and plasma concentration,
indicating that miR-155 may influence the pathogenesis of AD through its
effect on differentiation and function of Th17
cells\textsuperscript{42}. The expression changes and effects in cell
cultures of other miRNAs, including miR-151a\textsuperscript{43}, -143,
-124 and 10a are reported and outlined in \textbf{Table 1} . Altogether,
the studies of miRNAs in AD clearly demonstrate that miRNAs affect the
severity of skin inflammation, modulate cellular responses of
keratinocytes and specialized immune cells and thereby influence the
pathogenesis of AD.

\textbf{Allergic rhinitis}

AR also known as hay fever, represents the most common allergic disease
and is characterized by increased circulating IgE levels and/or positive
skin prick test. This is triggered by various environmental allergens
including pollen, molds, house dust mite and animal dander, and results
in a cascade of type 2 immune response in which type 2 cytokine
production and eosinophil numbers are increased . AR manifests in the
upper airways and often coexists with asthma\textsuperscript{44}.
Indeed, an estimated 10-40\% of AR patients suffer from
asthma\textsuperscript{45}. Mucosal inflammation in AR and asthma shares
many features, which has led to the ``united airway
concept''\textsuperscript{46} and the idea that inflammation in AR can
progressively extend to the lower airways\textsuperscript{47}. Even
though AR and asthma often co-exist, many studies examining AR subjects
aimed to uncover unique AR-specific miRNA signatures (\textbf{Table 2}
). Indeed, a subset of circulating miRNAs in plasma, miR-206, -338-3p,
-329 and -26a, were found to be differentially expressed in patients
with AR, but not in healthy individuals or those with non-allergic
asthma. Random forest model prediction suggested that a subset of six
miRNAs allowed for high accuracy in distinguishing between these three
groups\textsuperscript{48}.

In nasal biopsies, out-off-season AR patients displayed higher miR-7 and
miRPlus-E1194 expression, whereas let-7, miR-498,-187, -874, -143, -886,
-224, and -767 were decreased compared to non-allergic patients
undergoing inferior turbinate surgery\textsuperscript{49,50}. The
reduced levels of let-7e were confirmed by an additional study, which
also showed increased levels of miR-155, a miRNA involved in type 2
immune responses (see above\textsuperscript{51,52}), miR-205 and miR-498
in nasal biopsies of patients with current AR
symptoms\textsuperscript{50}. miR-498 was also increased in the nasal
mucosa of subjects suffering from perennial allergy, while miR-18a
expression was significantly lower in subjects with perennial allergy
compared to subjects with sensitization to seasonal
allergens\textsuperscript{48}.

The correlation of miRNAs with AR symptom severity (Total Nasal Symptoms
Score) revealed 3 down-regulated (miR-572, -1228-, -483) and 9
up-regulated miRNAs in nasal mucosa (miR-1908, -126, -92a, -125a, 19a,
26a, 106a, -181c, -3177). Of the identified miRNAs, miR-126, -19a and
-26a specifically and sensitively predicted AR disease activity in a
receiver operating characteristic (ROC) analysis\textsuperscript{53},
thus suggesting that miRNAs may be potential biomarkers in the prognosis
of AR.

\textbf{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 (\textbf{Table 3} ).

Allergic asthma often begins in early life with up to half of adults
reporting asthma symptoms beginning in childhood\textsuperscript{54}.
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
children\textsuperscript{55}. 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 asthma\textsuperscript{56-58}. 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)\textsuperscript{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 AR\textsuperscript{14}.
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 asthma\textsuperscript{15}. miR-21 has been commonly found to be
dysregulated in allergic asthma, both in the circulation and in the
airways of humans and mice\textsuperscript{8-10}. 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 \textsuperscript{16}. Another prevalent miRNA in asthma,
miR-19a has been shown to be a player in asthmatic
airways\textsuperscript{57,59,60}. 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
remodeling\textsuperscript{57,59}. In a recent study, decreased
epithelial and sputum miR-221 were associated with eosinophilic airway
inflammation in asthma\textsuperscript{61}. 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
sera\textsuperscript{62}.

Numerous biomarker studies have been conducted to find both
extracellular vesicle derived miRNAs from bronchoalveolar lavage (BAL)
and cell-specific miRNAs dysregulated in asthma\textsuperscript{63-65}.
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. \emph{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 assay\textsuperscript{66}. Bioinformatic
analysis of miRNA targets from the blood of house dust mite allergic
asthmatic children revealed enrichment in the PI3K and NF-\selectlanguage{greek}κ\selectlanguage{english}B 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 pathogenesis\textsuperscript{67}. Additionally, miRNA
expression in asthma has been correlated to expression and/or targeting
of the type 2 cytokines\textsuperscript{59,68}, IL-13
\textsuperscript{69}and IL-5\textsuperscript{70}, as well as
VEGF\textsuperscript{71}, 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.

Environmental Factors

\emph{miRNAs in the regulation of virus-induced asthma exacerbation}

Viruses affecting the respiratory system, such as human rhinoviruses
(RVs), respiratory syncytial virus (RSV) and influenza, are known to
cause serious illness and exacerbation in asthma
patients\textsuperscript{72-74}. When infecting human bronchial
epithelial cells (HBECs), these viruses activate the NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway and
interferon signaling in order to induce cellular responses, restrict
virus replication and avoid tissue damage. It has been suggested that
HBECs of asthmatic patients might have weakened interferon responses,
resulting in increased viral propagation, enhanced activation of NF-\selectlanguage{greek}κ\selectlanguage{english}B
and immune responses and asthma exacerbations\textsuperscript{75}. In
this context, it can be envisioned that miRNAs targeting the NF-\selectlanguage{greek}κ\selectlanguage{english}B
pathway and influencing interferon singnaling may have great potential
to modulate cellular responses to respiratory viruses and influence the
exacerbation of asthma. Accordingly, one of the earliest studies
addressing the question of miRNA involvement in the regulation of viral
responses showed an increase in viral replication of RV-1B in HBECs when
DICER was knocked down and, additionally, miR-128 and -155 were
inhibited\textsuperscript{76}. Another study found that miR-18a, -27a,
-128 and -155 were downregulated in asthmatic HBECs and that
simultaneous knockdown of these four miRNAs led to a significant
increase in IL-8 and IL-6 expression\textsuperscript{77}. Differences in
the bronchial epithelium of asthmatic patients may also occur due to
epigenetic changes\textsuperscript{78}. miRNAs can influence genes
involved in epigenetic regulation or modification and may also influence
cellular responses to respiratory viruses. Indeed, a recent study
demonstrated the upregulation of miR-22 and downregulation of its target
genes histone deacetylase (HDAC)4 and CD147 in response to influenza A
virus H1N1 in bronchial epithelial cells from healthy subjects. However,
cells from asthmatic patients were incapable of upregulating miR-22 and
showed increased and unchanged levels of HDAC4 and CD147,
respectively\textsuperscript{79}. Several additional studies suggest
important functions for miRNAs in the regulation of cellular and immune
responses to respiratory viruses (\textbf{Table 4} ). One example are
three miRNAs from different families (miR-24, -124a, -744) that all
interfere with the p38 MAPK pathway, through the downstream kinases MK2
and Myc. MK2 and Myc are essential pro-viral host factors and their
downregulation by these miRNAs (or small interfering RNA (siRNAs))
confers broad-spectrum antiviral activity against influenza A virus, RSV
and adenovirus\textsuperscript{80}. Most studies, however, are performed
in immortalized bronchial epithelial cells and rarely utilize primary
respiratory epithelial cultures, clinical samples or \emph{in vivo}
mouse models. Thus, information about the real role of miRNAs in
respiratory viral infections and virus-induced asthma exacerbations
remains very limited.

\emph{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
exacerbations\textsuperscript{81-89}. 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
\textsuperscript{90}. Since exposure to air pollution alters miRNA
expression both in the lungs and in blood (reviewed
in\textsuperscript{91}), 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 (\textbf{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 exhaust\textsuperscript{92}. 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 expression\textsuperscript{93}. In Chinese children,
increased miR-155 in the serum of asthmatic children correlated with
particulate matter level exposure\textsuperscript{94}. 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
symptoms\textsuperscript{95}. 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
development\textsuperscript{96}. This miRNA was also identified in
induced sputum of patients with severe asthma (both atopic and
non-atopic) and was associated with increased
neutrophils\textsuperscript{97}. In lung tissue of murine models with
\emph{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 only\textsuperscript{98,99}. 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 exposure\textsuperscript{100}. 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-\selectlanguage{greek}κ\selectlanguage{english}B signaling and epithelial to mesenchymal
transition (\textbf{Figure 2} )\textsuperscript{101-113}. miRNAs
reported to be involved in chronic obstructive pulmonary disease
(reviewed in \textsuperscript{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.

Mechanistic Studies

The availability of miRNA -mimics, -inhibitors and -knock out (KO)
murine lines in particular have helped to delineate the impact of
deregulated miRNA expression on disease pathology and revealed intricate
interactions of altered miRNA-regulation (\textbf{Table 6} ).

\emph{miRNAs in innate immune responses in allergic airway inflammation}

The exposure to allergens, e.g. house dust mite (HDM), is an important
trigger for changes in lung-specific miRNA expression. Allergen contact
triggers epithelial release of IL-33, which in turn tightly controls the
activation and proliferation of innate lymphoid type 2 cells (ILC2).
ILC2s provide early release of type 2 -promoting IL-5 and IL-13 and
initiate allergic airway inflammation. Studies in miRNA-KO mice revealed
the importance of miRNAs in these early pathogenetic events. Mice
deficient in miR-155 exposed to allergen had reduced levels of IL-33 in
the airways post allergen challenge and lower ILC2 numbers compared to
wild-type mice, revealing a critical role in inducing ILC2
proliferation\textsuperscript{117}. In dendritic cells (DC), lack of
miR-155 led to reduced chemotaxis and type 2-priming capacity, resulting
in ameliorated hallmarks of experimental
asthma\textsuperscript{41,118,119 120}. A similar phenotype was observed
for ILC2s recovered from miR17\textasciitilde{}92 cluster deficient
mice. These cells were found to be defective in growth and cytokine
expression in response to IL-33 and thymic stromal lymphopoietin
(TSLP)\textsuperscript{121}. However, further studies revealed the
complexity within miRNA-clusters, showing that individual family members
can have opposing roles. For example, within the
miR-17\textasciitilde{}92 cluster, the family member mir-19a was found
to be elevated in allergic inflammation and shown to promote IL-5 and
IL-13 production by targeting the known inhibitors SocS1 and
A20\textsuperscript{121}. In contrast, miR-19b was downregulated in
allergic inflammation and shown to target Tslp. Treatment with miR-19b
was able to reduce allergic inflammation, providing evidence for a
suppressive role and limiting type 2-inflammation\textsuperscript{122}.
Another miRNA induced in the murine airway upon allergen contact and
Toll-like receptor (TLR) signalling was miR-126. Inhibition of miR-126
using antagomirs was sufficient to suppress the inflammatory response,
implicating a prominent role in driving type 2
inflammation\textsuperscript{123,124}. The inflammatory milieu in the
lung induced the expression of miR-21 in cells of the
monocyte/macrophage lineage and structural cells. miR-21 targets
IL-12p35 mRNA and thereby critically controls the type 1/ type 2 balance
in type 2-high (Ovalbumin {[}OVA{]}, HDM, \emph{Aspergillus fumigatus} )
and steroid-insensitive experimental asthma\textsuperscript{125-128}.
Furthermore, it was shown that inhibition of miR-9 in experimental
allergic, steroid resistant asthma models restored the steroid
sensitivity via targeting protein phosphatase 2 regulatory subunit B
(B56) \selectlanguage{greek}δ \selectlanguage{english}isoform (PPP2R5D)\textsuperscript{129}. miR-9 was also increased
in the sputum of patients with neutrophilic asthma, which is often
associated with steroid resistance. Additionally, miRNAs seem to control
macrophage differentiation into their intrinsic sub-phenotypes. Along
this line, miR-511 was increased in alternatively activated macrophages,
but decreased in pro-inflammatory macrophages\textsuperscript{130}. A
similar study identified an upregulation of miR-124 in alternatively
activated macrophages\textsuperscript{131} and in
CD14\textsuperscript{+}CD16\textsuperscript{+} monocytes of patients
with asthma compared to controls.

\emph{miRNAs controlling adaptive immunity in experimental asthma}

\emph{In vitro} studies in CD4\textsuperscript{+} T cells revealed a
dynamic change of miRNA expression upon activation of cells and
polarization into specialized CD4\textsuperscript{+}T cell
subsets\textsuperscript{132}. Some miRNAs involved in controlling the
polarization process are encoded in the polycistronic clusters Mirc11
and Mirc22, comprising miRs-23(a/b), -24 and -27(a/b). Bioinformatic
analyses revealed several genes in a gene-network upstream of IL-4 to be
among the targets for these miRNAs. In an acute model of experimental
asthma, mice bearing CD4\textsuperscript{+}T cells deficient in these
miRNAs developed an augmented type 2 response, including high type
2-cytokine levels and elevated eosinophil numbers in
BAL\textsuperscript{11,133}. Conversely, miR-145 expression was found
induced in inflamed lungs and seemed to actively promote and sustain the
inflammatory process. Indeed, blockade by antagomirs suppressed the
production of IL-5 and IL-13 in the lungs and inhibited the inflammatory
phenotype to an extent equal to dexamethasone \textsuperscript{134}.

Once established, the allergic phenotype is thought to stabilize and
reinforce itself by IL-13 production in the inflamed environment.
Cellular control mechanisms, that restrict IL-13 expression in the
airways, seem to be suppressed in allergic airway inflammation and
include the involvement of miRNAs. One example is the let-7 family of
miRNAs\textsuperscript{135}, all of which were found to be downregulated
in OVA-induced experimental asthma. Exogenous delivery of let-7 limited
eosinophil recruitment and histopathological alterations and
airway-reactivity to metacholine\textsuperscript{135}. Further examples
are miR-133a and miR-448-5p, that are both downregulated in OVA-induced
asthma lung tissue and directly target the genes IGF-1 receptor
(\emph{Igf1r} )\textsuperscript{136}and\selectlanguage{greek}\emph{Tgfβ1}\selectlanguage{english}
\textsuperscript{137}, respectively. Furthermore, overexpression of both
miRNAs was able to reduce remodelling associated genes.

\emph{Cell-based functional studies}

Several studies investigated miRNA-based molecular mechanisms \emph{ex
vivo} /\emph{in vitro} in different cell types involved in asthma
pathogenesis\textsuperscript{138-143}. miR-155 is one of the most
frequently investigated miRNAs in regards to asthma and AD. miR-155 was
shown to be induced by hyper-stretch in human bronchial epithelial
cells\textsuperscript{144} and targets Src homology 2 domain--containing
inositol 5-phosphatase 1 (SHIP1) production and activates Janus Kinase
(JNK) signaling leading to KC (the functional IL-8 paralog) secretion in
mouse models. miR-181b was observed to be decreased in bronchial
brushings and plasma from patients with asthma and inversely correlated
with eosinophil counts in sputum\textsuperscript{145}. Overexpressing
this miRNA in a bronchial epithelial cell line (BEAS-2B) confirmed the
regulation of the target Secreted Phospho Protein 1 (SPP1) and reduced
IL-13 induced secretion of IL-1\selectlanguage{greek}β \selectlanguage{english}and CC-Motif Chemokine Ligand 11
(CCL11). In this line, miR-181b was induced following addition of
dexamethasone. Further, miR-27b has been described to be decreased in
HDM induced experimental asthma, with a proposed function in the
regulation of the PI3K-AKT pathway via targeting Spleen Associated
Tyrosine Kinase (SYK) and Epidermal Growth Factor Receptor (EGFR) in a
bronchial epithelial cell line (16-HBE)\textsuperscript{55}.The let-7
miRNA family is also very abundant in the lung and their
inhibition\emph{in vivo} ameliorated murine experimental
asthma\textsuperscript{69}; in particular, let-7a was shown to regulate
IL-13 expression\textsuperscript{135} \emph{in vitro} . In concordance
to its effect in skin keratinocytes,\textsuperscript{35,36}miR-146a was
shown to have anti-inflammatory function in human lung alveolar
epithelial cell line A549\textsuperscript{146,147}and in
HBECs.\textsuperscript{148}

Besides epithelial cells, several studies have investigated
miRNA-regulated mechanisms in airway smooth muscle cells. \emph{In
vitro} stimulation of hASMCs with a cytokine cocktail (IL-1\selectlanguage{greek}β, \selectlanguage{english}TNF-\selectlanguage{greek}α,
\selectlanguage{english}IFN-\selectlanguage{greek}γ\selectlanguage{english}) caused an increase in miR-146a with the observed effect being
stronger in cells from asthmatic donors compared to healthy
controls\textsuperscript{149}. As inhibition of miR-146a increases
cyclooxygenase-2 (COX-2) levels and IL-1\selectlanguage{greek}β \selectlanguage{english}secretion by hASMCs, the
authors suggested that miR-146a may be an interesting anti-inflammatory
factor in asthma. In line with this study, upregulation of miR-145 in
hASMCs was demonstrated upon cytokine stimulation and was associated
with enhanced migration and proliferation\emph{in vitro}
\textsuperscript{150}. Inhibition of miR-145 reversed this effect
through the reduced expression of collagen type I and contractile
protein MHC via targeting of Kr\selectlanguage{ngerman}üppel-like factor 4 (KLF-4). Finally,
miR-21 was shown to modulate hASMCs proliferation \emph{in vitro} , via
targeting PTEN, as identified by lentiviral overexpression
experiments\textsuperscript{151}. miR-21 has been previously associated
with asthma development, mainly due its targeting of i.e.
IL-12p35\textsuperscript{125,152}, highlighting the multi-functional
roles of miRNAs in several cell types contributing synergistically to
asthma pathology.

\emph{miRNA effects in gene networks}

miRNA expression analyses from isolated cells, as well as in tissues
from disease models, revealed simultaneously altered expression for
several miRNAs. This implicates several parallel regulatory events which
are not captured by traditional miRNA-single target gene identification
methodologies. Recently, network methods have been utilized to assess
the outcome of miRNA-regulation from a global perspective, revealing
possible relationships between the miRNA-targets and the affected
pathways. An example is the generation of a comprehensive regulatory
miRNA-mRNA network of \emph{in vitro} differentiated type 2 and Th17
cells compared to naive CD4\textsuperscript{+} T cells. It identified a
strong involvement of the miR-106a\textasciitilde{}363 cluster in Th17
differentiation, with decreases particularly of miR-106a, miR-18b and
miR-363 in Th17 cells\textsuperscript{153}. Conversely, overexpression
of the aforementioned miRNAs led to decreased expression of their
confirmed target genes \emph{Nuclear Factor of Activated T cells (Nfat5}
), \emph{RAR related Orphan Receptor C (Rorc),} and\emph{Rora} ; leading
to decreased Th17 differentiation and IL-17 secretion and identifying
this miRNA cluster as a potential target for Th17-mediated inflammation.
Th17 cell differentiation is also controlled by the
miR-17\textasciitilde{}92 cluster, in particular by
miR-18a\textsuperscript{154}, which targets Smad4, hypoxia-inducible
factor 1a (Hif1a), and Rora. Thus, miR-18a deficiency enhances Th17
differentiation \emph{in vitro} and increases Th17 cells in tissue in
experimental asthma models \emph{in vivo} .

Another approach identified a distinct miRNA-expression pattern in
tissue resident type 2 cells in experimental allergic asthma.
CD4\textsuperscript{+} type 2 cells displayed a strong downregulation of
miRNAs compared to naïve CD4\textsuperscript{+} T
cells\textsuperscript{155} and the expression pattern changed with the
transition from acute to chronic airway inflammation. Integrating gene-
and miRNA-expression using a network approach, revealed distinct disease
stage specific gene-miRNA networks\textsuperscript{155}. Pathogenic type
2 responses resulted from combined and cumulative activities of miRNAs,
integrating the net effect of induced miR-27b and miR-23b, targeting
immune regulatory Tgfb1 and Egfr pathways on the one hand. On the other
side, silenced miRNA activity (miR-206, miR-106b and miR-203), allowed
the expression of genes involved in immune activation. Antagonizing the
\emph{ex vivo} miRNA-expression levels using miRNA-inhibitors and mimics
suppressed IL-13 expression in Th2 cells.

\textbf{Conclusion}

miRNA research, thus far, has led to a breadth of information and long
lists of potentially interesting miRNAs, but mechanistic studies of
miRNA targeting and function are only beginning to emerge. Furthermore,
it is unlikely that one miRNA alone holds the key to explain the
pathology of asthma or allergic diseases, as it is not possible to
outline a single trigger. More likely, there are numerous players and
complex networks of interactions that lead not only to disease
pathogenesis, but also to heterogeneity, making mechanistic insight into
the roles of miRNAs all the more important going forward. We propose
that understanding common triggers for changes in miRNA expression in
distinct cell populations, at defined disease stages and in specific
phenotypes, together with assessing the net effects of miRNAs will help
to decipher the pathophysiological consequences of altered miRNA
expression in allergic diseases. Nonetheless, we have provided important
evidence highlighting a crucial role of miRNA in the pathogenesis of
asthma and allergic disease, making them interesting targets for
clinical investigations. Besides therapeutic strategies to target single
miRNA\textsuperscript{123,124,134,156-158}, there is increasing interest
in using miRNA profiles as biomarkers for (lung)
disease\textsuperscript{48,58,62,159-163}, which we will address in
detail in a future review.

\textbf{Word count: 4694 including headers (without abstract)}

\textbf{Figure legends}

Figure 1: Overview of miRNAs discussed in this review

miRNAs are important regulators in allergic diseases. Herein we provide
an overview of the miRNAs described within the review and the cell types
or organ systems where evidence of their actions have been reported. All
miRNAs have been examined in human cells unless indicated in \emph{bold
italics} (mouse studies) or \emph{underlined italics} (human and mouse).

Figure 2: The effect of air pollution on miRNA networks and pathways in
airway epithelial cells.

Shown is a detailed schematic of miRNA action including known
targets.Increased miRNA expression is indicated with upward red arrow,
decreased miRNA expression is indicated with downward blue arrow. Black
arrows indicate a stimulatory effect on expression or process, black
line ending with perpendicular line indicate inhibitory effect. Based on
references 66-101.

\textbf{Table 1. The functions of miRNAs in atopic dermatitis}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{miRNA} & \textbf{Function} &
\textbf{Targets\textsuperscript{\#}} &
\textbf{References}\tabularnewline
\midrule
\endhead
\textbf{miR-21} & Upregulated in AD & N.D. &
~\textsuperscript{33}\tabularnewline
\textbf{miR-146a} & Upregulated in the skin and keratinocytes of AD
patients; alleviates chronic inflammation in a mouse model of AD &
IRAK1, CARD10, CCL5 & ~\textsuperscript{34-36,38-40,164}\tabularnewline
\textbf{miR-155} & May influence the development of AD by downregulating
CTLA-4 in T cells and by modulation of the development of Th17 cells &
CTLA-4, SOCS1 & ~\textsuperscript{37,42,76}\tabularnewline
\textbf{miR-151a} & Altered in the blood plasma of AD patients, may
contribute to Th2 skewing and pathogenesis of AD & IL12RB2 &
~\textsuperscript{165}\tabularnewline
\textbf{miRNA-143} & May reduce the influence of IL-13 on epidermal
keratinocytes & IL-13R\selectlanguage{greek}α\selectlanguage{english}1 & ~\textsuperscript{166}\tabularnewline
\textbf{miR-124} & Suggested to decrease inflammation in chronic AD skin
lesions & p65 & ~\textsuperscript{167}\tabularnewline
\textbf{miR-223} & Upregulated in whole blood of AD patients & ~N.D. &
~\textsuperscript{143}\tabularnewline
\textbf{miR-10a} & Upregulated in AD skin, inhibits keratinocyte
proliferation & MAP3K7, HAS3 & ~\textsuperscript{168}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{\#}N.D. -- Not determined in publications cited in the
current table, may be described by other studies.

\textbf{Table 2: miRNAs in allergic rhinitis}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{miRNA} & \textbf{Function} &
\textbf{Targets\textsuperscript{\#}} &
\textbf{References}\tabularnewline
\midrule
\endhead
\textbf{let-7} & \textbf{Major regulatory mechanism for modulation IL-13
secretion and thereby type-2 inflammation} & \textbf{JAK1/STAT3 , IL-13,
SOCS4} & \textsuperscript{\textbf{50,}
\textbf{135;50,169}}\tabularnewline
\textbf{miR-206} & \textbf{Regulator of the VEGF pathway} &
\textbf{S100A7A} & \textsuperscript{\textbf{48}}\tabularnewline
& & \textbf{VEGF} &\tabularnewline
\textbf{miR-338-3p} & \selectlanguage{greek}\textbf{Inhibitor of Wnt/β-catenin signaling and
inducer of epithelial-mesenchymal transition}\selectlanguage{english} & \selectlanguage{greek}\textbf{WNT/ β
-Catentin}\selectlanguage{english} & \textsuperscript{\textbf{48}}\tabularnewline
\textbf{miR-329} & \textbf{Unknown} & \selectlanguage{greek}\textbf{TGF-β1}\selectlanguage{english} &
\textsuperscript{\textbf{48}}\tabularnewline
\textbf{miR-26a} & \selectlanguage{greek}\textbf{modulation of TGF-β-dependent signalling
pathways and repression of inflammatory responses by promoting
regulatory T cell responses or through NF-κB inhibition}\selectlanguage{english} &
\textbf{SMAD2, SMAD3} & \textsuperscript{\textbf{48}}\tabularnewline
\textbf{miR-7} & \textbf{Unknown} & \textbf{CMKLR1} &
\textsuperscript{\textbf{49}}\tabularnewline
\textbf{miR-498} & \textbf{Suppressing Th17 cell differentiation via
STAT3} & \textbf{STAT3} &
\textsuperscript{\textbf{48,50}}\tabularnewline
\textbf{miR-187} & \textbf{Regulation of T cell response via CD276} &
\textbf{CD276} & \textsuperscript{\textbf{49,50}}\tabularnewline
\textbf{miR-143} & \textbf{Regulates memory T cell differentiation} &
\selectlanguage{greek}\textbf{TGF-β1}\selectlanguage{english} & \textsuperscript{\textbf{49,50}}\tabularnewline
\textbf{miR-886} & \textbf{Regulates TGF pathway via SMAD3} &
\textbf{SMAD3, FoxO1} & \textsuperscript{\textbf{49,50}}\tabularnewline
\textbf{miR-224} & \textbf{Regulates TGF pathway via SMAD4} &
\textbf{SMAD4} & \textsuperscript{\textbf{49,50}}\tabularnewline
\textbf{miR-155} & \textbf{Important role in host defense, modulates
IL-13 pathway in macrophages determining the M2 phenotype} &
\textbf{IL13Ra1} & \textbf{}\tabularnewline
\textsuperscript{51,52,170,171} & & &\tabularnewline
\textbf{miR-205} & \textbf{Activation of ERK17 pathway} &
\textbf{MICAL2} & \textsuperscript{\textbf{50}}\tabularnewline
\textbf{miR-572} & \textbf{Regulates type-1 cytokine expression} &
\textbf{SOCS1} & \textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR-1228} & \textbf{Regulates type 2 responses} & \textbf{PPAR}
& \textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR-483} & \selectlanguage{greek}\textbf{Inhibition of TGFβ1}\selectlanguage{english} & \selectlanguage{greek}\textbf{TGFβ1}\selectlanguage{english} &
\textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR-1908} & \selectlanguage{greek}\textbf{Inhibition of TGFβ1}\selectlanguage{english} & \textbf{SMAD2, SMAD3}
&\tabularnewline
MMP2 & \textsuperscript{\textbf{53}} & &\tabularnewline
\textbf{miR-126} & \textbf{Counter-regulation of IL4 effect} &
\textbf{VEGF, IRS1} & \textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR-92a} & \textbf{Regulation of IL4 effect} & \textbf{WNT5a} &
\textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR-125a} & \textbf{Dampens down TLR pathway via IL10,
suppresses A20} & \textbf{TLR, A20} &
\textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR-19a} & \selectlanguage{greek}\textbf{Activates TGFβ signaling}\selectlanguage{english} & \selectlanguage{greek}\textbf{TGFβ1}\selectlanguage{english} &
\textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR-106a} & \textbf{Regulation of authophagic activity} &
\textbf{NOD1/2} & \textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR-181c} & \textbf{Down-regulates Osteopontin, modulating TGF}
& \textbf{Osteopontin} & \textsuperscript{\textbf{53}}\tabularnewline
\textbf{miR18a} & \textbf{Regulating TGF pathway} & \textbf{CTGF} &
\textsuperscript{\textbf{48}}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3. miRNAs in asthma -- studies using patient samples and
cell cultures}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{miRNA}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Function or findings}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Targets\textsuperscript{\#}}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{References}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-15b, 126, -139,-142, -186,-191, -342, -374a, -409, -660,
-942, -1290}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Circulating miRNAs (blood) correlating to lung function parameters in
children\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{56}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-16, -30d, -296}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Circulating miRNAs (blood) correlating to bronchial
hyperresponsiveness\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{57}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-146a, -206, -720}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Circulating miRNAs (blood) used in combination as potential asthma
prediction markers\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{58}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-16, -125b, -133b, -206, -299}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Plasma miRNAs able to distinguish asthmatics from healthy individuals or
those with allergic rhinitis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{48}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{let-7a, miR-21, -133a, -155, -328, -1248}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Decreased in exhaled breath condensates from asthmatic compared to
healthy subjects\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{68}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-21}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Dysregulated in circulation and lungs in allergic experimental murine
models and human allergic asthmatics,\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{9-11}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-155}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulated in the lymphocytes of allergic asthmatics during pollen
season\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{172}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{miR-19a}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Increased in airway T cells Reduction in smooth muscle cells leads to
enhanced remodeling\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
PTEN, A20\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textsuperscript{57,59}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-221}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Decreased levels in epithelial and sputum was associated with
eosinophilic airway inflammation in asthma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{61}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-185}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Identified in circulating eosinophils as a distinguisher between healthy
and asthmatic subjects. A potential predictor of asthma severity in
blood sera.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N.D.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{62}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-16}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Negatively correlates to lung function parameters\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ADRB2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{66}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-223, -513a and -625}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulated in the blood of dust mite allergic asthmatics compared to
healthy individuals\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CBL, PPARGC1B, ESR1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{55}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{let-7a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abundant in the lungs and regulates IL-13 expression\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IL-13\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{69}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-1248}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Interacts with the 3'UTR to promote IL-5 expression\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IL-5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{70}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-15a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Low levels in CD4+ T cells in pediatric asthma subject\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
VEGF\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{71}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-146a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulated in bronchial brushing samples of asthma patients, inhibits
IL-8 and CXCL1 expression and neutrophil migration\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IRAK1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{148}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{\#}N.D. -- not determined in publications cited in the
current table, may be described by other studies

\textbf{Table 4. miRNAs and respiratory viruses}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{miRNA}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Function}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Targets}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{References}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
miR-155\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Inhibition results in increased replication of RV-1B in HBECs
Overrepresented in extracellular vesicles of children with RV
infection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
SOCS1 SHIP-1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textsuperscript{76,80}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
miR-22\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
May influence cellular responses to influenza A virus H1N1 in asthmatic
HBECs\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
HDAC4, CD147 (?)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textsuperscript{79}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
miR-155,-27a, -18a, -128\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Altered in asthmatic HBECs, simultaneous knockdown results in increased
IL-8 and IL-6 Alter viral responses in bronchial epithelial cell
line\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
multiple\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textsuperscript{76}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miRNA-4776\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulation of the NF-\selectlanguage{greek}κ\selectlanguage{english}B inhibitor beta, increased Influenza A virus
survival in HBECs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NFKBIB\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{173}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-221\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulated in response to RSV, inhibits viral replication and
infectivity\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NGF, TrKA\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{174}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-23b\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulates very low density lipoprotein receptor and thereby inhibits
infection by minor group of RVs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
VLDLR, LRP5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{175}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-136\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Increased in A549 human lung epithelial cells infected with H5N1
influenza A virus, upregulates IFN-\selectlanguage{greek}β\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
RIG-I\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{176}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-29\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Induced in A549 cells by influenza A and PBMCs in influenza patients,
induces COX2 and IFN-\selectlanguage{greek}λ\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
DNMT3A\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{177}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-29c\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Induced by influenza in A549 cells, may contribute to virus-mediated
apoptosis, inhibits innate immune responses\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BCL2L2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{178,179}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-let-7c\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Upregulated in influenza infected A549 cells, may reduce virus
replication.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
viral M1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{180}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-449b\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Upregulated in influenza infected A549 cells, regulates antiviral
cytokine signaling\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
HDAC1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{181}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-3145\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
May inhibit influenza A viruses replication\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
viral PB1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{182}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
miR-485\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Prevents spurious activation of antiviral signalling, restricts
influenza virus H5N1 infection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
RIG-I, viral PB1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textsuperscript{183}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-144\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Attenuates the host response to influenza virus by targeting the
TRAF6-IRF7 signalling axis in HBECs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
TRAF6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{184}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-324-5p\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulated in A549 cells in response to infection with RNA viruses,
enhanced type I and III interferons and interferon-inducible genes\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CUEDC2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{185}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
miR-24 miR-124a miR-744\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Suppress influenza A (all) and RSV (miR-124a, miR-744) infection in A549
cells by inhibition of p38 MAPK expression and activation of MK2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
P38MAPK MK2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textsuperscript{63}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 5. miRNA studies investigating the relation between
pollution and allergy or asthma}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{miRNA}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Function or findings}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{References}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Human data\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
miR-183 miR-324 miR-132\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
In controlled exposures in atopic subjects (exposure chamber) , the
miRNA expression was modulated by allergen exposure, but not
additionally by diesel exposure\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textsuperscript{92}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
miR-21 (up) miR-30e (up) miR-215 (up) miR-144 (up)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
In controlled exposures in asthma patients (exposure chamber), diesel
exposure was associated with increased expression of miR-21, miR-30e,
miR-215 and miR-144. miR-144 and miR-21 associated with systemic
oxidative stress markers and negative correlation between miR-144 and
antioxidant genes\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textsuperscript{93}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
miR-199a1 (down)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
miR-199a controls AXL (receptor kinase of the TAM (TYRO3, AXL, MERTK)
family. Maternal smoking is associated with increased methylation of AXL
and with reduced expression of miR-199a. Combination of material smoking
and increased AXL methylation alters the risk of childhood bronchitis
symptoms.\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textsuperscript{95}.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
miR-223 (up)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Prenatal tobacco exposure is associated with high miR-223 expression in
cord and maternal blood with low Treg numbers\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textsuperscript{96}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Murine data\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
miR-221 (up) miR-16 (up) miR-130 (down)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
In a model cigarette-aggravated allergic asthma (in utero side stream
cigarette smoke, followed by \emph{Aspergillus fumigatus} exposure), the
altered miRNAs are associated with apoptosis and anti-angiogenesis
pathways\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textsuperscript{98}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
miR-155 (up) miR-21 (up) miR-18 (up)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
In a model cigarette-aggravated allergic asthma (in utero side stream
cigarette smoke, followed by \emph{Aspergillus fumigatus} exposure),
these miRNAs are positively associated with Type2 cytokines in
bronchoalveolar lavage fluid\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textsuperscript{99}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 6. miRNAs and mouse models}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{miRNA}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Function}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Target}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{References}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-21}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Induced by Th2 cytokines in DC and macrophages and promotes type 2-
driven inflammation.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IL-12p35\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{125-128}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-126}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Induced in airway wall and promotes type 2 inflammation.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
TOM1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{123,124}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{let-7a-e}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulated in CD4+ T cells and suppresses type 2 inflammation.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IL-13\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{135}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR- 145}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Induced by allergen exposure and promotes type 2 inflammation.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{134}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{miR-155}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Induced in ILC2 in type 2 inflamed airways and neutralization
ameliorates experimental asthma phenotype. Involved in Th2 mediated
airway inflammation.\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
S1pr1 PU.1(?)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textsuperscript{41,117-120}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-23\textasciitilde{}27}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Type 2 cells lacking this miR-cluster express elevated type 2
cytokines.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Gene network regulating IL-4\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{11,133}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR17-92}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mice deficient in this miR-cluster develop an augmented experimental
asthma phenotype.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
~\textsuperscript{121}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-19a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Upregulated in asthmatic airways and promotes experimental asthma.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
SOCS1/ A20\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{59}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{miR-19b}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Downregulated in asthmatic airways. Exogenous delivery of miR-19b mimics
ameliorate experimental asthma.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
TSLP\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textsuperscript{122}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{miR network} \textbf{miR-27b (up)} \textbf{miR-206 (down)}
\textbf{miR-106b (down)} \textbf{miR-203 (down)} \textbf{miR-23b
(up)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
A miR-network is induced in lung resident type 2 cells and comprises a
combination of induced miRs-27b and -23b as well as silenced miR-206,
miR106b and miR-203. Antagonism of expression levels reduces type 2
cytokine expression.\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Fine tuning of multiple pathways, that suppress inhibitory signals and
allow activation and survival of type 2 cells\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textsuperscript{155}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

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CUEDC2. \emph{J Virol.} 2018;92(19).\selectlanguage{english}
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