ABSTRACT
MiR-511-3p is embedded in intron 5 of the CD206/MRC1 gene Mrc1, expressed by macrophage and dendritic cell populations. CD206 and miR-511-3p expression are co-regulated, and their contribution to intestinal inflammation is unclear. We investigated their roles in intestinal inflammation in both mouse and human systems. Colons of CD206-deficient mice displayed normal numbers of monocytes, macrophage, and dendritic cells. In experimental colitis, CD206-deficient mice had attenuated inflammation compared with wild-type (WT) mice. However, neither a CD206 antagonist nor a blocking antibody reproduced this phenotype, suggesting that CD206 was not involved in this response. Macrophages isolated from CD206-deficient mice had reduced levels of miR-511-3p and Tlr4 compared with WT, which was associated with reduced pro-inflammatory cytokine production upon lipopolysaccharides (LPS) and fecal supernatant stimulation. Macrophages overexpressing miR-511-3p showed 50% increase of Tlr4 mRNA, whereas knockdown of miR-511-3p reduced Tlr4 mRNA levels by 60%, compared with scrambled microRNA (miRNA)-transduced cells. Response to anti-tumor necrosis factor (TNF) treatment has been associated with elevated macrophage CD206 expression in the mucosa. However, in colon biopsies no statistically significant change in miR-511-3p was detected. Taken together, our data show that miR-511-3p controls macrophage-mediated microbial responses and is involved in the regulation of intestinal inflammation.
Subject(s)
Colitis/immunology , Colon/immunology , Macrophages/immunology , Membrane Glycoproteins/genetics , MicroRNAs/genetics , Receptors, Cell Surface/genetics , Animals , Cells, Cultured , Colitis/chemically induced , Dextran Sulfate , Female , Gene Expression Regulation , Humans , Lipopolysaccharides/immunology , Male , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Cell Surface/metabolism , Receptors, Immunologic , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolismABSTRACT
Intestinal epithelial cells (IECs) are integral players in homeostasis of immunity and host defense in the gut and are under influence of the intestinal microbiome. Microbial metabolites and dietary components, including short chain fatty acids (acetate, propionate, and butyrate, SCFAs), have an impact on the physiology of IECs at multiple levels, including the inhibition of deacetylases affecting chromatin remodeling and global changes in transcriptional activity. The number and diversity of butyrate-producing bacteria is subject to factors related to age, disease, and to diet. At physiological levels, SCFAs are inhibitors of histone deacetylases (HDACs) which may explain the transcriptional effects of SCFAs on epithelial cells, although many effects of SCFAs on colonic mucosa can be ascribed to mechanisms beyond HDAC inhibition. Interference with this type of post-translational modification has great potential in cancer and different inflammatory diseases, because HDAC inhibition has anti-proliferative and anti-inflammatory effects in vitro, and in in vivo models of intestinal inflammation. Hence, the influence of dietary modulators on HDAC activity in epithelia is likely to be an important determinant of its responses to inflammatory and microbial challenges.