Therapeutic role of TLR9 agonist in the atherosclerosis

Abstract

Background: 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 the role of TLR9 in atherosclerosis. Methods and Results: Newly generated double-knockout ApoE−/−:TLR9−/− mice and control ApoE−/− mice were fed a high-fat diet from 8 weeks of age and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15 and 20 weeks. All four 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 VLDL/LDL cholesterol, the VLDL/LDL:HDL ratio was unaltered because of a parallel increase in plasma HDL 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 ODN) to ApoE−/− mice resulted in a reduction of lesion severity. Conclusions: Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE−/− mice. CD4+ T-cells were identified as potential mediators of this effect. A type B CpG ODN TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.