A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation

Cell Signal. 2008 Dec;20(12):2266-75. doi: 10.1016/j.cellsig.2008.08.022. Epub 2008 Sep 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cells, Cultured
  • Foam Cells / drug effects
  • Foam Cells / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • NADH, NADPH Oxidoreductases / metabolism*
  • NADPH Oxidase 1
  • NF-kappa B / metabolism
  • Oligodeoxyribonucleotides / pharmacology
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Reactive Oxygen Species / metabolism
  • Receptors, Scavenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Scavenger Receptors, Class E / agonists
  • Scavenger Receptors, Class E / metabolism*
  • Signal Transduction
  • Time Factors
  • Toll-Like Receptor 9 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • CpG ODN 2216
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • Olr1 protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptors, Scavenger
  • Scavenger Receptors, Class E
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidase 1
  • NOX1 protein, mouse
  • p38 Mitogen-Activated Protein Kinases