miRNA effects in gene networks
miRNA expression analyses from isolated cells, as well as in tissues
from disease models, revealed simultaneously altered expression for
several miRNAs. This implicates several parallel regulatory events which
are not captured by traditional miRNA-single target gene identification
methodologies. Recently, network methods have been utilized to assess
the outcome of miRNA-regulation from a global perspective, revealing
possible relationships between the miRNA-targets and the affected
pathways. An example is the generation of a comprehensive regulatory
miRNA-mRNA network of in vitro differentiated type 2 and Th17
cells compared to naive CD4+ T cells. It identified a
strong involvement of the miR-106a~363 cluster in Th17
differentiation, with decreases particularly of miR-106a, miR-18b and
miR-363 in Th17
cells153. Conversely,
overexpression of the aforementioned miRNAs led to decreased expression
of their confirmed target genes Nuclear Factor of Activated T
cells (Nfat5 ), RAR related Orphan Receptor C (Rorc), andRora ; leading to decreased Th17 differentiation and IL-17
secretion and identifying this miRNA cluster as a potential target for
Th17-mediated inflammation. Th17 cell differentiation is also controlled
by the miR-17~92 cluster, in particular by
miR-18a154, which
targets Smad4, hypoxia-inducible factor 1a (Hif1a), and Rora. Thus,
miR-18a deficiency enhances Th17 differentiation in vitro and
increases Th17 cells in tissue in experimental asthma models in
vivo .
Another approach identified a distinct miRNA-expression pattern in
tissue resident type 2 cells in experimental allergic asthma.
CD4+ type 2 cells displayed a strong downregulation of
miRNAs compared to naïve CD4+ T
cells155 and the
expression pattern changed with the transition from acute to chronic
airway inflammation. Integrating gene- and miRNA-expression using a
network approach, revealed distinct disease stage specific gene-miRNA
networks155.
Pathogenic type 2 responses resulted from combined and cumulative
activities of miRNAs, integrating the net effect of induced miR-27b and
miR-23b, targeting immune regulatory Tgfb1 and Egfr pathways on the one
hand. On the other side, silenced miRNA activity (miR-206, miR-106b and
miR-203), allowed the expression of genes involved in immune activation.
Antagonizing the ex vivo miRNA-expression levels using
miRNA-inhibitors and mimics suppressed IL-13 expression in Th2 cells.