Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Meteria Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Acta Pharmacol Sin. 2013 Aug;34(8):1025-35. doi: 10.1038/aps.2013.75. Epub 2013 Jul 15.
Toll-like receptor 2 (TLR2) signaling plays a critical role in the initiation of atherosclerosis. The aim of this study was to investigate whether blocking TLR2 activity could produce therapeutic effects on advanced atherosclerosis.
Forty-week old apolipoprotein E-deficient (ApoE(-/-)) mice fed on a normal diet were intravenously injected with a TLR2-neutralizing antibody or with an isotype-matched IgG for 18 weeks. Double-knockout ApoE(-/-)Tlr2(-/-) mice were taken as a positive control. At the end of the treatments, the plasma lipid levels were measured, and the plaque morphology, pro-inflammatory cytokines expression and apoptosis in arteries were analyzed. In the second part of this study, 6-week old ApoE(-/-) and ApoE(-/-)Tlr2(-/-) mice fed on a high-cholesterol diet for 12 to 24 weeks, the expression levels of TLR2 and apoptotic markers in arteries were examined.
Blockade of TLR2 activity with TLR2-neutralizing antibody or knockout of Tlr2 gene did not alter the plasma lipid levels in ApoE(-/-) mice. However, the pharmacologic and genetic manipulations significantly reduced the plaque size and vessel stenosis, and increased plaque stability in the brachiocephalic arteries. The protective effects of TLR2 antagonism were associated with the suppressed expression of pro-inflammatory cytokines IL-6 and TNF-α and the inactivation of transcription factors NF-κB and Stat3. In addition, blocking TLR2 activity attenuated ER stress-induced macrophage apoptosis in the brachiocephalic arteries, which could promote the resolution of necrotic cores in advanced atherosclerosis. Moreover, high-cholesterol diet more prominently accelerated atherosclerotic formation and increased the expression of pro-apoptotic protein CHOP and apoptosis in ApoE(-/-) mice than in ApoE(-/-)Tlr2(-/-) mice.
The pharmacologic or genetic blockade of TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in ApoE(-/-) mice. Thus, targeting TLR2 signaling may be a promising therapeutic strategy against advanced atherosclerosis.
Toll 样受体 2（TLR2）信号在动脉粥样硬化的起始中起着关键作用。本研究旨在探讨阻断 TLR2 活性是否对晚期动脉粥样硬化具有治疗作用。
40 周龄载脂蛋白 E 缺陷（ApoE（-/-））小鼠给予正常饮食，静脉注射 TLR2 中和抗体或同种型 IgG 18 周。双敲除 ApoE（-/-）Tlr2（-/-）小鼠作为阳性对照。治疗结束时，测量血浆脂质水平，并分析动脉粥样斑块形态、促炎细胞因子表达和细胞凋亡。在本研究的第二部分，6 周龄 ApoE（-/-）和 ApoE（-/-）Tlr2（-/-）小鼠给予高胆固醇饮食 12 至 24 周，检测动脉中 TLR2 和凋亡标志物的表达水平。
TLR2 中和抗体阻断 TLR2 活性或敲除 Tlr2 基因不改变 ApoE（-/-）小鼠的血浆脂质水平。然而，药物和基因操作显著减小了肱动脉斑块大小和血管狭窄程度，并增加了斑块的稳定性。TLR2 拮抗的保护作用与抑制促炎细胞因子 IL-6 和 TNF-α的表达以及转录因子 NF-κB 和 Stat3 的失活有关。此外，阻断 TLR2 活性可减轻肱动脉中内质网应激诱导的巨噬细胞凋亡，从而促进晚期动脉粥样硬化中坏死核心的溶解。此外，与 ApoE（-/-）Tlr2（-/-）小鼠相比，高胆固醇饮食更明显地加速了 ApoE（-/-）小鼠的动脉粥样硬化形成，并增加了促凋亡蛋白 CHOP 和凋亡的表达。
TLR2 活性的药物或基因阻断可减少和稳定 ApoE（-/-）小鼠的晚期动脉粥样硬化病变。因此，靶向 TLR2 信号可能是治疗晚期动脉粥样硬化的一种有前途的治疗策略。
