P043 Inhibition of miR-142-5P ameliorates disease in mouse models of experimental colitis
N. Duijvis*1, C. Kunne1, M. Slaman1, F. van Dooren1, E. Vogels1, S. Meijer2, K. Fluiter3, P. Moerland3, A. te Velde1
1Academic Medical Centre (AMC), Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands, 2Academic Medical Centre (AMC), Department of Pathology, Amsterdam, Netherlands, 3Academic Medical Centre (AMC), Department of Clinical Epidemiology, Amsterdam, Netherlands
MicroRNA’s regulate genes involved in the immune response, and may be of importance in the pathogenesis of inflammatory bowel disease (IBD). By their mechanism of action, microRNAs (miRNAs) can be promising new therapeutic targets. The aim of this study was to determine the role of miRNAs in this model of chronic experimental colitis.
Colitis caused by transfer of WT CD4+CD45RBhi T-cells in severe combined immunodeficiency (SCID) mice shares many features with human inflammatory bowel disease (IBD). At 3 time points, miRNA from the colon were assessed from 3 colitic mice, and a time-dependent up regulation of a number of miRNAs was seen. To inhibit these miRNA functions, specific locked-nucleic-acid-modified (LNA) oligonucleotides were administered in further experiments, at the moment the mice demonstrated the first signs of disease, that is 3 weeks after the transfer of the CD4+CD45RBhi T-cells. As a control, a scrambled sequence of anti-miRNA was used.
Our data suggests that anti-miR-142-5p administration reduced colitis in this model, reflected in reduced weight loss and a lower disease activity index (DAI). In further experiments, we observed a higher survival rate, a lower DAI, and less colonic histological inflammation in mice treated with this compound also in male RAG1-/- mice. Moreover, by mRNA microarray, we found downstream activation of the IL10RA pathway, with 4 of the top-10 identified candidate target genes of miR-142-5p affected within. Three candidate target genes have been described previously as susceptibility genes in IBD.
The IL10RA is regulated by miR-142-5p, and it plays a role in our model of chronic experimental colitis. Knocking down miR-142-5p reduces symptoms of colitis.