MicroRNA-511-3p mediated modulation of the peroxisome proliferator-activated receptor gamma (PPARγ) controls LPS-induced inflammatory responses in human monocyte derived DCs

Abstract

AbstractThe peroxisome proliferator activated receptor gamma (PPARγ) is a ligand activated transcription factor expressed in dendritic cells (DCs), where it exerts anti-inflammatory responses against TLR4-induced inflammation. Recently, microRNA-511 (miR-511) has also emerged as a key player in controlling TLR4-mediated signalling, and in regulating the function of DCs. Interestingly, PPARγ has been previously highlighted as a putative target of miR-511 activity; however the link between miR-511 and PPARγ and its influence on human DC function within the context of LPS-induced inflammatory responses is unknown. Using a selection of miR-511-3p-specific inhibitors and mimics, we demonstrate for the first time that up or downregulation of miR-511-3p inversely correlates with PPARγ mRNA levels and transcriptional activity following treatment with PPARγ synthetic agonist rosiglitazone (RSG), in the presence or absence of LPS. Additionally, we show that PPARγ activation with RSG modulates LPS-induced DC activation and downregulates pro-inflammatory cytokine production following downregulation of miR-511-3p. Lastly, PPARγ activation was shown to suppress LPS-mediated induction of indoleamine 2,3-dioxygenase (IDO) activity in DCs, most likely due to changes in miR-511-3p expression. These data suggest that PPARγ-induced modulation of DC phenotype and function is influenced by miR-511-3p expression, which may serve as a potential therapeutic target against inflammatory diseases.