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.