Journal Article

Regulation of miRNA Transcription in Macrophages in Response to Candida albicans

Hutvagner, György, Monk, Claire E., Arthur, J. Simon C.

2010

Overview

Macrophages detect pathogens via pattern recognition receptors (PRRs), which trigger several intracellular signaling cascades including the MAPK and NFκB pathways. These in turn mediate the up-regulation of pro-inflammatory cytokines that are essential to combat the pathogen. However as the over-production of pro-inflammatory cytokines results in tissue damage or septic shock, precise control of these signaling pathways is essential and achieved via the induction of multiple negative feedback mechanisms. miRNAs are small regulatory RNAs that are able to affect protein expression, via the regulation of either mRNA stability or translation. Up-regulation of specific miRNAs could have the potential to modulate PRR signaling, as has been shown for both miR-146 and miR-155. Here we have analysed which miRNAs are up-regulated in mouse macrophages in response to the fungal pathogen heat killed Candida albicans and compared the profile to that obtained with the TLR4 ligand LPS. We found that in addition to miR-146 and miR-155, both Candida albicans and LPS were also able to up-regulate miR-455 and miR-125a. Analysis of the signaling pathways required showed that NFκB was necessary for the transcription of all 4 pri-miRNAs, while the ERK1/2 and p38 MAPK pathways were also required for pri-miR-125a transcription. In addition the anti-inflammatory cytokine IL-10 was found to be able to induce miR-146a and b, but inhibited miR-155 induction. These results suggest that miR-455, miR-125, miR-146 and miR-155 may play important roles in regulating macrophage function following PRR stimulation.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animals / Base Sequence / Candida albicans / Candida albicans - immunology / Cascades / Cell Biology/Cell Signaling / Cells, Cultured / Cytokines / DNA Primers / Extracellular signal-regulated kinase / Feedback / Fungal infections / Gene expression / Gene Expression Regulation / Gene regulation / Immune system / Immunology/Innate Immunity / Immunology/Leukocyte Signaling and Gene Expression / Inflammation / Interleukin 10 / Interleukin-10 - physiology / Intracellular signalling / Kinases / Life sciences / Ligands / Lipopolysaccharides / Lipopolysaccharides - pharmacology / Macrophages / Macrophages - drug effects / Macrophages - metabolism / MAP kinase / MAP Kinase Signaling System / Mice / MicroRNA / MicroRNAs / MicroRNAs - genetics / miRNA / mRNA stability / Negative feedback / Neurophysiology / NF-kappa B - metabolism / NF-κB protein / Oligonucleotide Array Sequence Analysis / Pathogens / Pathways / Pattern recognition / Pattern recognition receptors / Phosphorylation / Proteins / Receptors / Regulations / Reverse Transcriptase Polymerase Chain Reaction / Septic shock / Signal Transduction / TLR4 protein / Toll-like receptors / Transcription / Transcription (Genetics) / Transcription, Genetic / Translation (Genetics)