Unexpected protective role for Toll-like receptor 3 in the arterial wall
Unexpected protective role for Toll-like receptor 3 in the arterial wall
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DOI：
10.1073/pnas.1018515108
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发表时间：
2011-02-08
影响因子：
11.1
通讯作者：
Monaco, Claudia
中科院分区：
文献类型：
--
作者：
Cole, Jennifer E.;Navin, Tina J.;Monaco, Claudia
Toll样受体在哺乳动物宿主防御中的重要作用近年来得到了广泛的研究。大约10个TLR识别许多细菌和病毒病原体上的保守模式的能力是显著的。由于受体如此之少，与自身组织成分的交叉反应经常发生。以前的研究经常分配有害作用的TLR，特别是TLR 2和TLR 4，在免疫和心血管疾病。使用人类和小鼠系统，我们研究了TLR 3信号传导在血管疾病中的后果。我们比较了人动脉粥样硬化源性平滑肌细胞（AthSMC）和对照主动脉平滑肌细胞（AoSMC）对各种TLR配体的反应。AthSMC表现出TLR 3表达和TLR 3依赖性功能反应的特异性增加。有趣的是，在体外和体内暴露于dsRNA诱导血管细胞和组织中促炎基因和抗炎基因的表达增加。因此，我们试图评估TLR 3信号转导在机械性和高胆固醇血症诱导的动脉损伤中的作用。令人惊讶的是，通过以TLR 3依赖性方式全身施用dsRNA类似物Poly（I：C）减少了血管周围颈诱导的损伤模型中的新生内膜形成。此外，TLR 3的基因缺失显著增强了颈损伤后弹性膜损伤的发展。因此，TLR 3的缺乏加速了高胆固醇血症ApoE（-/-）小鼠动脉粥样硬化的发生。总的来说，我们的数据描述了TLR信号在血管壁中的保护作用。
The critical role of Toll-like receptors (TLRs) in mammalian host defense has been extensively explored in recent years. The capacity of about 10 TLRs to recognize conserved patterns on many bacterial and viral pathogens is remarkable. With so few receptors, cross-reactivity with self-tissue components often occurs. Previous studies have frequently assigned detrimental roles to TLRs, in particular to TLR2 and TLR4, in immune and cardiovascular disease. Using human and murine systems, we have investigated the consequence of TLR3 signaling in vascular disease. We compared the responses of human atheroma-derived smooth muscle cells (AthSMC) and control aortic smooth muscle cells (AoSMC) to various TLR ligands. AthSMC exhibited a specific increase in TLR3 expression and TLR3-dependent functional responses. Intriguingly, exposure to dsRNA in vitro and in vivo induced increased expression of both pro-and anti-inflammatory genes in vascular cells and tissues. Therefore, we sought to assess the contribution of TLR3 signaling in vivo in mechanical and hypercholesterolemia-induced arterial injury. Surprisingly, neointima formation in a perivascular collar-induced injury model was reduced by the systemic administration of the dsRNA analog Poly(I: C) in a TLR3-dependent manner. Furthermore, genetic deletion of TLR3 dramatically enhanced the development of elastic lamina damage after collar-induced injury. Accordingly, deficiency of TLR3 accelerated the onset of atherosclerosis in hypercholesterolemic ApoE(-/-) mice. Collectively, our data describe a protective role for TLR signaling in the vessel wall.