Abstract
BackgroundToll-like receptors (TLR) of the innate immune system have been closely linked with the development of atherosclerotic lesions. TLR9 is activated by unmethylated CpG motifs within ssDNA, but also by CpG motifs in nucleic acids released during vascular apoptosis and necrosis. The role of TLR9 in vascular disease remains controversial and we sought to investigate the effects of a proinflammatory TLR9 stimulation in mice.Methods and FindingsTLR9-stimulation with high dose CpG ODN at concentrations between 6.25nM to 30nM induced a significant proinflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid and increased numbers of circulating endothelial microparticles, as a marker for amplified endothelial damage. Chronic TLR9 agonism in apolipoprotein E-deficient (ApoE-/-) mice fed a cholesterol-rich diet increased aortic production of reactive oxygen species, the number of circulating endothelial microparticles, circulating sca-1/flk-1 positive cells, and most importantly augmented atherosclerotic plaque formation when compared to vehicle treated animals. Importantly, high concentrations of CpG ODN are required for these proatherogenic effects.ConclusionsSystemic stimulation of TLR9 with high dose CpG ODN impaired reendothelialization upon acute vascular injury and increased atherosclerotic plaque development in ApoE-/- mice. Further studies are necessary to fully decipher the contradictory finding of TLR9 agonism in vascular biology.
Highlights
Atherosclerosis is a chronic inflammatory disease, characterized by apoptosis and necrosis of vascular cells such as endothelial cells, smooth muscle cells and macrophages
These danger signals are detected by specialized pattern recognition receptors (PRR) and trigger innate immune mechanisms to promote the clearance of detritus and to engage potential cytotoxic substances [1]
As part of the innate immune system, PRR detect structures of bacterial and viral pathogens, termed pathogen-associated molecular patterns (PAMP), and initiate an intracellular signaling cascade leading to the release of proinflammatory cytokines
Summary
Atherosclerosis is a chronic inflammatory disease, characterized by apoptosis and necrosis of vascular cells such as endothelial cells, smooth muscle cells and macrophages. As part of the innate immune system, PRR detect structures of bacterial and viral pathogens, termed pathogen-associated molecular patterns (PAMP), and initiate an intracellular signaling cascade leading to the release of proinflammatory cytokines. One such PRR, Toll-like-receptor (TLR) 9 is located in the endosomes of resident vascular cells, such as endothelial and smooth muscle cells, cardiomyocytes, cardiac fibroblasts, and of professional immune cells, including macrophages, B-cells and plasmacytoid dendritic cells [2,3,4,5,6,7]. The role of TLR9 in vascular disease remains controversial and we sought to investigate the effects of a proinflammatory TLR9 stimulation in mice
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