Abstract
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.
Highlights
The innate immune system is able to detect infection via the recognition of various pathogen specific molecules, referred to as pathogen derived molecular patterns or PAMPs
To determine if fungal ligands were able to up-regulate miRNAs, murine bone marrow derived macrophages (BMDMs) were stimulated with heat killed C. albicans for 16 hours
Analysis of the relative expression of these miRNAs before and after stimulation with heat killed C. albicans showed that the expression of most of these was unaffected by treatment
Summary
The innate immune system is able to detect infection via the recognition of various pathogen specific molecules, referred to as pathogen derived molecular patterns or PAMPs. Recognition of PAMPs occurs via specific groups of ‘pathogen recognition receptors’ or PRRs, including Toll-like receptors (TLRs), Nodlike receptors, CARD domain helicases such as RIG-I and C-type lectins such as dectin-1. Recognition of PAMPs occurs via specific groups of ‘pathogen recognition receptors’ or PRRs, including Toll-like receptors (TLRs), Nodlike receptors, CARD domain helicases such as RIG-I and C-type lectins such as dectin-1 Each of these receptors is specific for certain PAMPs, and different pathogens will be sensed by different combinations of PRRs (reviewed in [1,2,3]). In addition to the positive signals provided by the pathogens and pro-inflammatory cytokines themselves, multiple inhibitory feedback mechanisms act on inflammatory cytokine production, including direct negative feedback mechanisms in PRR activated signaling cascades and the production of anti-inflammatory cytokines such as IL-10
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