Abstract
BackgroundAccumulating evidence implicates a fundamental link between the immune system and atherosclerosis. Toll-like receptors are principal sensors of the innate immune system. Here we report an assessment of the role of the TLR2 pathway in atherosclerosis associated with a high-fat diet and/or bacteria in ApoE+/− mice.Methods and ResultsTo explore the role of TLR2 in inflammation- and infection-associated atherosclerosis, 10 week-old ApoE+/−-TLR2+/+, ApoE+/−-TLR2+/− and ApoE+/−-TLR2−/− mice were fed either a high fat diet or a regular chow diet. All mice were inoculated intravenously, once per week for 24 consecutive weeks, with 50 µl live Porphyromonas gingivalis (P.g) (107 CFU) or vehicle (normal saline). Animals were euthanized 24 weeks after the first inoculation. ApoE+/−-TLR2+/+ mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE+/−-TLR2+/− and ApoE+/−-TLR2−/− mice for all diet conditions. They also displayed profound changes in plaque composition, as evidenced by increased macrophage infiltration and apoptosis, increased lipid content, and decreased smooth muscle cell mass, all reflecting an unstable plaque phenotype. SAA levels from ApoE+/−-TLR2+/+ mice were significantly higher than from ApoE+/−-TLR2+/− and ApoE+/−-TLR2−/− mice. Serum cytokine analysis revealed increased levels of pro-inflammatory cytokines in ApoE+/−-TLR2+/+ mice compared to ApoE+/−-TLR2+/− and TLR2−/− mice, irrespective of diet or bacterial challenge. ApoE+/−-TLR2+/+ mice injected weekly for 24 weeks with FSL-1 (a TLR2 agonist) also demonstrated significant increases in atherosclerotic lesions, SAA and serum cytokine levels compared to ApoE+/−-TLR2−/− mice under same treatment condition. Finally, mass-spectrometry (MALDI-TOF-MS) of aortic samples analyzed by 2-dimentional gel electrophoresis differential display, identified 6 proteins upregulated greater than 2-fold in ApoE+/−-TLR2+/+ mice fed the high fat diet and inoculated with P.g compared to any other group.ConclusionGenetic deficiency of TLR2 reduces diet- and/or pathogen-associated atherosclerosis in ApoE+/− mice, along with differences in plaque composition suggesting greater structural stability while TLR-2 ligand-specific activation triggers atherosclerosis. The present data offers new insights into the pathophysiological pathways involved in atherosclerosis and paves the way for new pharmacological interventions aimed at reducing atherosclerosis.
Highlights
Atherosclerosis is a multifactorial chronic inflammatory disease characterized by the accumulation of cells of both the innate and acquired immune systems within the intima of the arterial wall [1,2]
The present data offers new insights into the pathophysiological pathways involved in atherosclerosis and paves the way for new pharmacological interventions aimed at reducing atherosclerosis
No significant differences in body weight were observed in mice in connection to genotype or treatment, (e.g. P. g, FSL-1)
Summary
Atherosclerosis is a multifactorial chronic inflammatory disease characterized by the accumulation of cells of both the innate and acquired immune systems within the intima of the arterial wall [1,2]. The normal homeostatic functions of the endothelium are altered, promoting an inflammatory response that results in increased expression of adhesion molecules This in turn leads to recruitment of leukocytes, including monocytes, which penetrate into the intima, predisposing the vessel wall to lipid accretion [1,3,4]. Macrophages and endothelial cells (EC) express receptors that recognize a broad range of molecular patterns foreign to the mammalian organism but commonly found on pathogens. These molecules include lipopolysaccharides and lipoproteins from Gramnegative bacteria, peptidoglycan and lipoteichoic acids from Grampositive bacteria, lipoproteins from mycoplasma, and zymosan from yeast [9]. We report an assessment of the role of the TLR2 pathway in atherosclerosis associated with a high-fat diet and/or bacteria in ApoE+/2 mice
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