Open AccessInhibition of miR-142-5P ameliorates disease in mouse models of experimental colitis
Author(s) -
Nicolette W. Duijvis,
Perry D. Moerland,
Cindy Kunne,
Monique M. W. Slaman,
Faas H. van Dooren,
Esther Vogels,
Wouter J. de Jonge,
Sybren L. Meijer,
Kees Fluiter,
Anje A. te Velde
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0185097
Subject(s) - colitis , inflammatory bowel disease , microrna , inflammation , pathogenesis , cancer research , downregulation and upregulation , biology , immunology , gene , medicine , disease , genetics
Background MicroRNAs (miRNAs) are epigenetically involved in regulating gene expression. They may be of importance in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to determine the role of miRNAs by their specific blocking in the CD4+CB45RB hi T-cell transfer model of chronic experimental colitis. Methods Colitis caused by transfer of WT CD4+CD45RB hi T cells in severe combined immunodeficiency (SCID) mice shares many features with human IBD. Colonic miRNA expression levels were measured at three time points in colitic mice, where a time-dependent upregulation of multiple miRNAs was seen. To inhibit these miRNAs, specific locked-nucleic-acid-modified (LNA) oligonucleotides were administered in further experiments at the moment the mice demonstrated the first signs of colitis. As controls, PBS and a scrambled sequence of anti-miRNA were used. Genome-wide expression analyses were also performed in order to detect candidate target genes of miR-142-5p, of which inhibition resulted in most effective amelioration of colitis. Results Anti-miR-142-5p reduced colitis and related wasting disease when administered in the T-cell transfer model, reflected in reduced weight loss and a lower disease activity index (DAI). In further validation experiments we also observed a higher survival rate and less colonic histological inflammation in the antagomir-treated mice. Moreover, by genome-wide expression analyses, we found downstream activation of the anti-inflammatory IL10RA pathway, including three genes also found in the top-20 candidate target genes of miR-142-5p. Conclusion In conclusion, CD4+CD45RB hi -transfer colitis induces miR-142-5p. Blocking miR-142-5p reduced colitis and prevented wasting disease, possibly by activation of the IL10RA pathway.