From the Department of Cell Biology & Atherosclerosis (C.K., Y.C.C., C.H., I.A., T.S.K., C.T., A.B., K.P., A.A.) and Department of Diabetic Complications (C.K., T.A., K.J.-D.), Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Cardiology and Angiology I, Heart Centre Freiburg University, Freiburg, Germany (I.A.); Molecular Cell Biology Division, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia (M.J.S.); Laboratory of Host Defense, WPI Immunology Frontier Research Centre, Osaka University, Osaka, Japan (S.A.); and Department of Immunology, Monash University, Melbourne, Victoria, Australia (A.B., K.P., A.A.).
Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):516-25. doi: 10.1161/ATVBAHA.113.302407. Epub 2014 Jan 16.
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.
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.
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.
动脉粥样硬化是由与固有免疫系统共享的炎症反应驱动的。Toll 样受体-9（TLR9）是固有免疫系统的一种细胞内模式识别受体，目前作为炎症性疾病的治疗靶点正在进行临床研究。在这里，我们研究了 TLR9 是否在载脂蛋白 E 缺陷（ApoE（-/-））小鼠的动脉粥样硬化发展中起作用。
新生成的双重敲除 ApoE（-/-）：TLR9（-/-）小鼠和对照 ApoE（-/-）小鼠从 8 周开始喂食高脂肪饮食，并在 8、12、15 和 20 周后评估对病变大小、细胞组成、炎症状态和血浆脂质的影响。所有 4 个时间点均显示 ApoE（-/-）：TLR9（-/-）小鼠的动脉粥样硬化病变严重程度加剧，相应增加了脂质沉积和巨噬细胞、树突状细胞和 CD4（+）T 细胞的积累。尽管 ApoE（-/-）：TLR9（-/-）小鼠的血浆极低密度脂蛋白/低密度脂蛋白胆固醇增加，但极低密度脂蛋白/低密度脂蛋白：高密度脂蛋白比值不变，因为血浆高密度脂蛋白胆固醇的平行增加。作为解释 ApoE（-/-）：TLR9（-/-）小鼠斑块进展的潜在机制，进一步研究了 CD4（+）T 细胞的积累，并在 ApoE（-/-）：TLR9（-/-）小鼠中耗尽这些细胞，显著降低了病变严重程度。作为最终的转化方法，给 ApoE（-/-）小鼠施用 TLR9 激动剂（B 型 CpG 寡脱氧核苷酸 1668）可降低病变严重程度。
在喂食高脂肪饮食的 ApoE（-/-）小鼠中，固有免疫受体 TLR9 的基因缺失加剧了动脉粥样硬化。CD4（+）T 细胞被鉴定为这种作用的潜在介导物。B 型 CpG 寡脱氧核苷酸 TLR9 激动剂可降低病变严重程度，从而为动脉粥样硬化提供了一种新的治疗方法。
