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
proliferation117. In
dendritic cells (DC), lack of miR-155 led to reduced chemotaxis and type
2-priming capacity, resulting in ameliorated hallmarks of experimental
asthma41,118,119
120. A similar phenotype was observed
for ILC2s recovered from miR17~92 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)121. However,
further studies revealed the complexity within miRNA-clusters, showing
that individual family members can have opposing roles. For example,
within the miR-17~92 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
A20121. 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-inflammation122.
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
inflammation123,124.
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, Aspergillus
fumigatus ) and steroid-insensitive experimental asthma125-128. 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) δ isoform
(PPP2R5D)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
macrophages130. A
similar study identified an upregulation of miR-124 in alternatively
activated
macrophages131 and in
CD14+CD16+ monocytes of patients
with asthma compared to controls.