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Page 2 of 16 Weidner et al. J Transl Genet Genom 2019;3:2. I https://doi.org/10.20517/jtgg.2018.30

complexity of the disease phenotypes necessitates the definition of pathophysiological mechanisms driving
[7]
different subtypes of asthma, i.e., classified as a disease endotype .

In recent years, the role of non-coding RNAs has emerged as an important area of research. Particularly,
microRNAs (miRNAs) are prime examples of regulatory molecules with roles in a variety of different
diseases such as cancer, multiple sclerosis, diabetes, and pulmonary disease [9-14] . miRNAs target messenger
RNA (mRNA) transcripts through binding of conserved seed sequences. A single miRNA can regulate many
different mRNAs in a spatial and temporal manner. Additionally, several miRNAs may target the same
mRNA transcript, although not necessarily under the same conditions. Regulation occurs mainly through
the silencing of a transcript by translational repression or targeting of the particular mRNA for decay [15,16] .
For more details regarding metazoan miRNA biogenesis, targeting, and function, several excellent reviews
have been recently published [17-19] . Although miRNAs are not new players in disease development, their role
as regulatory molecules in asthma is a relatively new field of study. miRNAs are extremely stable in a variety
of bodily fluids such as blood, urine, sputum, exhaled breath condensates, serum and plasma, facilitating
their study via non-invasive methods [20-24] . Due to the ever growing list of miRNAs being discovered and
verified, the complexity of miRNA regulation is far from being unraveled.

Although there have been several advancements in our knowledge of asthma, particularly in the control and
treatment of symptoms, many questions remain regarding the molecular mechanisms of the disease. In this
review, we aim to discuss the current knowledge regarding the role of miRNAs in asthma, from mouse to man.

Evidence for miRNA regulation in asthma models
[25]
Animal models are useful tools for the study of asthma pathogenesis . However, no mouse model
encompasses all features of asthma including severe asthma. For instance, mice do not spontaneously
[26]
develop a disease that resembles human asthma . To mimic the human disease, both ovalbumin (OVA)-
induced and house dust mite-induced murine models of allergic airway inflammation were developed [27,28] .
As a consequence, the human allergic asthma phenotype has been the main asthma subtype studied in
the mouse models. Type 2 allergic immune responses in humans are mediated by the type 2 cytokines,
[29]
interleukin (IL)-4, IL-5 and IL-13, which also occurs in the mouse model . CD4+ T-helper 2 cells (Th2
cells) are thought to play a central role in regulating phenotypes of allergic asthma; however, during the last
decade innate lymphoid cells (ILCs) have also been discovered. In addition to Th2 cells, ILC2 cells produce
significant amounts of the type 2 cytokines IL-5 and IL-13 [30-32] .

T cells
Cell-specific miRNA expression patterns in murine models have suggested a role for miRNAs in lineage
commitment and T cell effector functions [33,34] . Deletion of essential components of the miRNA biosynthesis
[35]
pathway has revealed a critical role for miRNAs in T cell activation and function . Interestingly, in T cells
lacking Dicer, a key protein in the biosynthesis of miRNAs, an enhanced differentiation towards Th cell
and cytokine production was seen. This suggests an important role for miRNAs in naïve T cell homeostasis.
However how these processes are regulated are still under further investigation.

[36]
Recent studies have identified that the miR-23~27~24 cluster controls T cell differentiation and function .
By combining loss and gain-of-function genetic approaches, the authors demonstrated that the miR-
23~27~24 cluster regulated Th2 differentiation and effector function in vivo in mice. Thus, two independent
reports revealed that miR-24 and miR-27 inhibited Th2 differentiation and IL-4 production [36,37] . Deletion of
these miRNAs promoted Th2-dependent responses in vivo in an OVA-induced allergic asthma model. miR-
24 directly targeted the 3’-untranslated region (3’ UTR) of IL-4 whereas miR-27 was shown to repress GATA
binding protein 3 (Gata3), Ikaros family zinc finger 1 and nuclear factor of activated T cells 2 (Nfatc2), all of
which are positive regulators of IL-4 expression. Interestingly, induced expression of miR-24 promoted Th1
[36]
and Th17 differentiation and induced T regulatory cells . These data suggested that individual miRNAs