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.