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lavage in human asthma [50,51] , however, the exact mechanisms underlying ILC2 development and
function are currently unknown. One recent study demonstrated that the miR-17~92 cluster regulates
different aspects of ILC2 biology. Mice deficient in the miR-17~92 cluster in ILC2s displayed reduced lung
[52]
inflammation following papain exposure . Furthermore, the miR-17~92 cluster member miR-19a promoted
IL-5 and IL-13 production in ILC2s and inhibited several targets including suppressor of cytokine signaling
1 (SOCS1) and tumor necrosis factor alpha induced protein 3 (Tnfaip3), both of which are known negative
regulators of IL-5 and IL-13 production. These findings clearly demonstrate miRNAs important regulators
of ILC2 biology in addition to T cells. We have further demonstrated in an OVA-model of allergic airway
inflammation that miR-155 deficient mice display impaired numbers of ILC2s in the airways and that miR-
[45]
155 deficiency affects IL-33 signaling . Thus, miR-155 was shown to be required for IL-33-induced ILC2
expansion and function in vivo. Indeed, IL-33 stimulation upregulated miR-155 in wild type ILC2s more
than 10-fold and ILC2s derived from miR-155 deficient mice produced less IL-13 upon IL-33 stimulation
compared to wild type derived ILC2s. Interestingly, in a recent study, miR-155 was shown to regulate ILC2
survival following activation by protecting ILC2s from apoptosis to promote type-2 immunity. By using
mixed bone marrow chimeras, the authors clearly demonstrated that an ILC2-intrinsic expression of miR-
155 is required to protect ILC2s from apoptosis, confirming our study that miR-155 is required for ILC2
[53]
expansion in vivo .
The airway
Both miR-126 and miR-145 have been shown to be expressed in the airway wall. One of the first studies
[54]
describing functionality of a miRNA in an animal model of asthma was by Mattes et al. demonstrating
a significant role for miR-126 in HDM-driven allergic airway inflammation. In their study, miR-126
was shown to be upregulated in the airway wall following HDM challenge and inhibition of miR-126 by
miR-126 antagomirs, reducing the effector functions of Th2 cells and the development of allergic airway
[54]
inflammation . Similarly, inhibition of miR-145 attenuated the production of IL-5 and IL-13 by Th2 cells,
eosinophil recruitment, mucus hypersecretion and airway hyper-responsiveness in HDM-induced allergic
[55]
inflammation . miR-106a has been shown to inhibit the anti-inflammatory cytokine IL-10 expression in both
[56]
lymphoid and myeloid cells. Sharma et al. were among the first to describe the targeting of IL-10 by miR-
106a and its role as a potential therapeutic by reversing the asthmatic phenotype. Administration of miR-106a-
specific antagomir locally to the airways in an OVA-model of allergic asthma reduced inflammation and Th2
[56]
responses, airway hyper-responsiveness, goblet cell metaplasia and subepithelial fibrosis .

Evidence for miRNAs regulation in steroid-insensitive asthma models
miRNA-directed therapeutics for asthma and allergic diseases are areas of investigations. Several studies as
mentioned above, clearly demonstrate that miRNAs are capable of altering both airway inflammation and
airway hyper-responsiveness in in vivo studies of allergic eosinophilic asthma models. However, most of
the studies conducted are in acute models of allergic asthma - steroid-insensitive asthma is often associated
with a non-eosinophilic phenotype- and infection-driven forms even though subgroups of eosinophilic
[57]
inflammation exist. In a mouse model of steroid-resistant asthma Li et al. demonstrated that miR-
9 antagonism restored dexamethasone sensitivity. miR-9 expression was shown to be increased in lung
macrophages and miR-9 directly targeted protein phosphatase 2A and thus interfered with glucocorticoid
[57]
signaling . Interestingly, miR-9 was also demonstrated to be increased in sputum from neutrophilic
asthma, but not in eosinophilic asthma. In another study of an infection-induced severe steroid-insensitive
experimental asthma model, miR-21 was shown to act upstream phosphoinositide-3-kinase (PI3K) signaling
pathway. miR-21 targeted phosphatase and tensin homolog (PTEN), thus amplifying PI3K-dependent
activity. Treatment with miR-21-specific antagomir or pan-PI3K inhibitor reduced PI3K activity and restored
histone deacetylase expression and led to suppression of airway hyper-responsiveness and steroid sensitivity
[58]
to allergic airway disease, highlighting miR-21 as a novel therapeutic target for this asthma group .

PEDIATRIC ASTHMA
The early work in mouse models has led the way for studies to be performed using human subjects. It was