Modulation of atherosclerosis in mice by Toll-like receptor 2
Modulation of atherosclerosis in mice by Toll-like receptor 2
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DOI：
10.1172/jci25482
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发表时间：
2005-11-01
影响因子：
15.9
通讯作者：
Curtiss, LK
中科院分区：
文献类型：
--
作者：
Mullick, AE;Tobias, PS;Curtiss, LK
流行病学证据已经确定了微生物感染和动脉粥样硬化之间的关系。哺乳动物TLR为这种炎症级联反应的机制提供了线索。TLR 2具有大的配体库，其包括细菌来源的外源性配体和可能的宿主来源的内源性配体。在动脉粥样硬化易感的低密度脂蛋白受体缺陷（Ldlr（-/-））小鼠中，TLR 2的完全缺陷导致动脉粥样硬化的减少。然而，在骨髓移植中，骨髓来源细胞TLR 2表达的丧失对疾病进展没有影响。这表明未知的内源性TLR 2激动剂通过激活非BM细胞来源的细胞中的TLR 2来影响病变进展。此外，腹膜内给予合成的TLR 2/TLR 1激动剂Pam 3CSK 4，Ldlr（-/-）小鼠的疾病负担显著增加。在Ldlr（-/-）小鼠中完全缺乏TLR 2，以及在Ldlr（-/-）小鼠中仅在BM衍生的细胞中缺乏TLR 2，导致对Pam 3CSK 4介导的动脉粥样硬化的显著保护，表明BM衍生的细胞表达TLR 2在转导外源性TLR 2激动剂的作用中的作用。这些研究支持慢性或复发性微生物感染可能导致动脉粥样硬化疾病的概念。此外，这些数据表明存在宿主来源的内源性TLR 2激动剂。
Epidemiologic evidence has established a relationship between microbial infection and atherosclerosis. Mammalian TLRs provide clues on the mechanism of this inflammatory cascade. TLR2 has a large ligand repertoire that includes bacterial-derived exogenous and possibly host-derived endogenous ligands. In atherosclerosis-susceptible low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, complete deficiency of TLR2 led to a reduction in atherosclerosis. However, with BM transplantation, loss of TLR2 expression from BM-derived cells had no effect on disease progression. This suggested that an unknown endogenous TLR2 agonist influenced lesion progression by activating TLR2 in cells that were not of BM cell origin. Moreover, with intraperitoneal administration of a synthetic TLR2/TLR1 agonist, Pam3CSK4, disease burden was dramatically increased in Ldlr(-/-) mice. A complete deficiency of TLR2 in Ldlr(-/-) mice, as well as a deficiency of TLR2 only in BM-derived cells in Ldlr(-/-) mice, led to striking protection against Pam3CSK4-mediated atherosclerosis, suggesting a role for BM-derived cell expression of TLR2 in transducing the effects of an exogenous TLR2 agonist. These studies support the concept that chronic or recurrent microbial infections may contribute to atherosclerotic disease. Additionally, these data suggest the presence of host-derived endogenous TLR2 agonists.