Role of Toll-Like Receptors in Atherogenesis

动脉粥样硬化是一种动脉壁的慢性炎症性疾病。这是通过研究确定的。 高脂血症小鼠特异性炎症基因缺失对疾病严重程度的影响，Toll样 先天免疫系统的受体(TLR)可以感知病原体并介导细胞激活， 在感染、炎症和动脉粥样硬化之间提供了重要的联系。我们发现TLR2- 介导的炎症影响低密度脂蛋白受体缺陷(LDLR-/-)的疾病进展 老鼠。促动脉粥样硬化性炎症TLR2介导的对未知内源性激动剂的反应是 非骨髓源性细胞包括内皮细胞、平滑肌细胞和血管内皮细胞的介导 成纤维细胞。相反，对已知的外源性合成TLR2的促动脉粥样硬化炎症反应 激动剂Pam3是由包括巨噬细胞在内的骨髓来源的细胞介导的。在此的项目4中 计划项目拨款我们将确认TLR2通过内源性或外源性介导的细胞激活 TLR2激动剂主要是致动脉粥样硬化，并分析TLR2介导的炎症如何影响 动脉硬化。在目标1中，我们将研究TLR2的内源性激动剂。我们将描述特定地区的特征 TLR2在非骨髓源性细胞中的体内表达及其作用的时间进程 TLR2对巨噬细胞渗入皮损的影响。我们将确定内源性致动脉粥样硬化的候选对象 并确定TLR2共受体、TLR1、TLR6和CD36在TLR2信号转导中的作用。在AIM 2 我们将研究TLR2的外源性激动剂。我们将确定巨噬细胞是否足以调节 明确的外源性激动剂引起的致动脉粥样硬化炎症。我们将定义TLR2的角色 与已知外源激动剂的共同受体。这些研究将加深我们对 动脉粥样硬化中的炎症反应和潜在的寻找新的TLR治疗靶点 减少疾病风险的干预措施。

Atherosclerosis is a chronic inflammatory disease of the arterial wall. THis has been established by studies of specific inflammatory gene deletions in hyperlipidemic mice that influence disease severity, the Toll-like receptors (TLR) of the innate immune system, which sense pathogens and mediate cell activation, can provide an important link between infection, inflammation and atherosclerosis. We discovered that TLR2- mediated inflammation influences disease progression in low density lipoprotein receptor-deficient (LDLr-/-) mice. Proatherogenic inflammatory TLR2-mediated responses to unknown endogenous agonists are mediated by non bone marrow-derived cells including endothelial cells, smooth muscle cells and advential fibroblasts. In contrast the proatherogenic inflammatory responses to the known exogenous, synthetic TLR2 agonist, Pam3, are mediated by bone marrow-derived cells including macrophages. In Project 4 of this program project grant we will confirm that TLR2-mediated cell activation by either endogenous or exogenous TLR2 agonists is predominately proatherogenic and analyze how TLR2-mediated inflammation influences atherosclerosis. In Aim 1 we will study endogenous agonists of TLR2. We will characterize region-specific expression of TLR2 in vivo in non-bone marrow-derived cells and document the time course of the effect of TLR2 on macrophage infiltration into lesions. We will identify candidate endogenoous proatherogenic agonists and define the role of the TLR2 co-receptors, TLR1, TLR6 and CD36 in TLR2 signaling. In Aim 2 we will study exogenous agonists of TLR2. We will determine if macrophages are sufficient for mediating proatherogenic inflammation induced by defined exogenous agonists. We will define the role of the TLR2 co-receptors with known exogenous agonists. These studies will enhance our understanding of inflammatory responses in atherosclerosis and potentially identify new TLR targets for therapeutic intervention to reduce disease risk.