The activation of liver X receptors inhibits toll-like receptor-9-induced foam cell formation.
Toll-like receptors (TLRs) are related to foam cell formation (FCF), key event in the establishment/progression of atherosclerosis. The activation of TLR2 and TLR4 can increase FCF. The aim of this study was to evaluate the role of TLR9 in FCF. Murine macrophages were treated with CpG-ODN, TLR9 agonist, and oxidized particles of LDL (Paz-PC) and FCF was analyzed by means of Oil Red O staining. The administration of CpG-ODN plus Paz-PC onto macrophages increased the amount of lipid droplets, correlated to increased levels of tumor necrosis factor (TNF)-alpha, IFNbeta, and IP-10. The underlying mechanism by which TLR9 ligation influenced Paz-PC in the FCF was NF-kappaB- and IRF7-dependent, as observed by higher levels of phosphorylated IkappaBalpha, increased nuclear translocation of the p65 subunit, lower levels of the total IKKalpha protein and higher release of interferon-dependent cytokines, such as IP-10. Liver X receptors (LXRs) regulate lipid cellular transport and negatively modulate TLR-dependent signaling pathways. Indeed, the addition of GW3965, synthetic LXRs agonist, significantly reduced FCF after CpG-ODN plus Paz-PC stimulation. In this condition, we observed decreased levels of the nuclear translocation of the p65 subunit, related to the higher presence of LXRalpha into the nucleus. TNF-alpha, IP-10, and IFNbeta levels were reduced by the administration of GW3965 following CpG-ODN and Paz-PC treatment. In conclusion, the activation of TLR9 facilitates the formation of foam cells in an NF-kappaB- and IRF7-dependent manner, countered by the activation of LXRs. This study further support LXRs as potential anti-atherosclerotic target.
Sorrentino
Rosalinda
R
Pharmaceutical Science Department, University of Salerno, 84084 Fisciano, Salerno, Italy. rosalinda.sorrentino@googlemail.com
Morello
Silvana
S
Chen
Shuang
S
Bonavita
Eduardo
E
Pinto
Aldo
A
D000818:Animals; D001391:Azo Compounds; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D004396:Coloring Agents; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D010766:Phosphorylation; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C528536:1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine; D001391:Azo Compounds; D001565:Benzoates; D001596:Benzylamines; C408982:CPG-oligonucleotide; D054357:Chemokine CXCL10; D004396:Coloring Agents; C473027:GW 3965; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D050839:Interferon Regulatory Factor-7; C494235:Irf7 protein, mouse; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000605214:Nr1h3 protein, mouse; D009838:Oligodeoxyribonucleotides; D057093:Orphan Nuclear Receptors; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D010767:Phosphorylcholine; D000072000:NF-KappaB Inhibitor alpha; D016899:Interferon-beta; C011049:oil red O