| First Author | Jongstra-Bilen J | Year | 2017 |
| Journal | J Immunol | Volume | 199 |
| Issue | 6 | Pages | 2149-2157 |
| PubMed ID | 28784845 | Mgi Jnum | J:254751 |
| Mgi Id | MGI:6103739 | Doi | 10.4049/jimmunol.1601363 |
| Citation | Jongstra-Bilen J, et al. (2017) Oxidized Low-Density Lipoprotein Loading of Macrophages Downregulates TLR-Induced Proinflammatory Responses in a Gene-Specific and Temporal Manner through Transcriptional Control. J Immunol 199(6):2149-2157 |
| abstractText | Hypercholesterolemia is a key risk factor for atherosclerosis and leads to the uptake of native and oxidized low-density lipoprotein (oxLDL) by macrophages (Mvarphis) and foam cell formation. Inflammatory processes accompany Mvarphi foam cell formation in the artery wall, yet the relationship between Mvarphi lipid loading and their response to inflammatory stimuli remains elusive. We investigated proinflammatory gene expression in thioglycollate-elicited peritoneal Mvarphis, bone marrow-derived Mvarphis and dendritic cells, and RAW264.7 cells. Loading with oxLDL did not induce peritoneal Mvarphi apoptosis or modulate basal-level expression of proinflammatory genes. Upon stimulation of TLR4, the rapid induction of IFN-beta was inhibited in cells loaded with oxLDL, whereas the induction of other proinflammatory genes by TLR4 (LPS), TLR3 (polyriboinosinic-polyribocytidylic acid), TLR2 (Pam3CSK4), and TLR9 (CpG) remained comparable within the first 2 h. Subsequently, the expression of a subset of proinflammatory genes (e.g., IL-1beta, IL-6, CCL5) was reduced in oxLDL-loaded cells at the level of transcription. This phenomenon was partially dependent on NF erythroid 2-related factor 2 (NRF2) but not on nuclear liver X receptors alpha and beta (LXRalpha,beta), peroxisome proliferator-activated receptor-gamma (PPARgamma), and activating transcription factor 3 (ATF3). LPS-induced NF-kappaB reporter activity and intracellular signaling by NF-kappaB and MAPK pathways were comparable in oxLDL-loaded Mvarphis, yet the binding of p65/RelA (the prototypic NF-kappaB family member) was reduced at IL-6 and CCL5 promoters. This study revealed that oxLDL loading of Mvarphis negatively regulates transcription at late stages of TLR-induced proinflammatory gene expression and implicates epigenetic mechanisms such as histone deacetylase activity. |
