Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice

Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):516-25. doi: 10.1161/ATVBAHA.113.302407. Epub 2014 Jan 16.

Abstract

Objective: Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice.

Approach and results: Newly generated double-knockout ApoE(-/-):TLR9(-/-) mice and control ApoE(-/-) mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE(-/-):TLR9(-/-) mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4(+) T cells. Although ApoE(-/-):TLR9(-/-) mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE(-/-):TLR9(-/-) mice, CD4(+) T-cell accumulation was further investigated and depletion of these cells in ApoE(-/-):TLR9(-/-) mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE(-/-) mice resulted in a reduction of lesion severity.

Conclusions: Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE(-/-) mice fed a high-fat diet. CD4(+) T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.

Keywords: CpG ODN; Toll-like receptor-9; atherosclerosis; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control
  • Apolipoproteins E / deficiency
  • Atherosclerosis / blood
  • Atherosclerosis / etiology
  • Atherosclerosis / immunology
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • CD4-Positive T-Lymphocytes / pathology
  • Cells, Cultured
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Dietary Fats / toxicity
  • Disease Progression
  • Lipoproteins, HDL / blood
  • Lipoproteins, VLDL / blood
  • Macrophages, Peritoneal / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligodeoxyribonucleotides / pharmacology
  • Oligodeoxyribonucleotides / therapeutic use
  • Random Allocation
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / physiology*

Substances

  • Apolipoproteins E
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Dietary Fats
  • Lipoproteins, HDL
  • Lipoproteins, VLDL
  • Oligodeoxyribonucleotides
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9