miRNAs controlling adaptive immunity in experimental asthma
In vitro studies in CD4+ T cells revealed a dynamic change of miRNA expression upon activation of cells and polarization into specialized CD4+T cell subsets132. 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+T cells deficient in these miRNAs developed an augmented type 2 response, including high type 2-cytokine levels and elevated eosinophil numbers in BAL11,133. 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 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 miRNAs135, 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 metacholine135. 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 (Igf1r )136andTgfβ1 137, respectively. Furthermore, overexpression of both miRNAs was able to reduce remodelling associated genes.