Genomic profile of human plasmacytoid dendritic cells exposed to oxidized LDL at baseline or after activation with CpG-A

Maturation and activation of plasmacytoid dendritic cells (pDCs), induced by the interaction of pathogens or trauma-derived danger signals, with pattern-recognition receptors, is a pivotal step in pDC innate and adaptive immune activation. Exposure to metabolites present in the pDC microenvironment may well influence critical signaling pathways in their function, and thereby tune host immune responses against endogenous, bacterial and viral pathogens. In this experiment, we have addressed the impact of hyperlipidemia on human pDCs at baseline and after activation. We show that exposure to pro-atherogenic (oxidized) low density lipoproteins led to pDC lipid accumulation, which in turn ablated Toll-like receptor (TLR) 7 and 9 dependent up-regulation of pDC maturation markers CD40, CD83, CD86 and HLA-DR. Transcriptional profiling and in vitro cell experiments revealed that, oxLDL exposure dampened TLR9 activation induced production of pro-inflammatory cytokines in a NUR77/IRF7 dependent manner and impaired the capacity of pDCs to prime and polarize CD4+ T helper (Th) cells. These results highlight the marked impact of hyperlipidemia on pDC responses to pathogen-derived signals. PDC were bead-isolated from human blood at >90% purity; pre-incubated with oxLDL or mock medium and then challenged with CpG, after which cells were lysed and total RNA was isolated.