A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation.
The formation of foam cells is the hallmark of early atherosclerotic lesions, and the uptake of modified low-density lipoprotein (LDL) by macrophage scavenger receptors is thought to be a key process in their formation. In this study, we examined the role of lectin-like oxLDL receptor-1 (Lox-1) and NADPH oxidase 1 (Nox1) in toll-like receptor 9 (TLR9)-mediated foam cell formation. TLR9 activation of Raw264.7 cells or mouse primary peritoneal macrophages by CpG ODN treatment enhanced Lox-1 gene and protein expression. In addition, CpG ODN-induced Nox1 mRNA expression, which in turn increased foam cell formation. The inhibition of CpG ODN-induced reactive oxygen species (ROS) generation by treatment with antioxidants, as well as with knockdown of Nox1 using siRNA, suppressed the formation of foam cells. The induction of Lox-1 and Nox1 by CpG ODN was regulated via the TLR9-p38 MAPK signaling pathway. CpG ODN also increased NFkappaB activity, and a potent inhibitor of NFkappaB that significantly blocked CpG-induced Nox1 expression, suggesting that Nox1 regulation is mediated through an NFkappaB-dependent mechanism. Taken together, these results suggest that a combination of Lox-1 and Nox1 plays a key role in the TLR9-mediated formation of foam cells via the p38 MAPK pathway.
Lee
Jin-Gu
JG
Aging-associated Vascular Disease Research Center, Department of Biochemistry & Molecular Biology, College of Medicine, Yeungnam University, 317-1 Daemyung-5 Dong, Nam-Gu, Daegu 705-717, South Korea.
Lim
Eun-Jung
EJ
Park
Dae-Weon
DW
Lee
Sun-Hye
SH
Kim
Jae-Ryong
JR
Baek
Suk-Hwan
SH
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000378:metabolism* / Q000819:agonists; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C526902:CpG ODN 2216; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; C495138:Olr1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051116:Receptors, Scavenger; D051127:Scavenger Receptors, Class E; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases