Innate Modulation of Macrophage Homeostasis

描述(由申请人提供)：巨噬细胞动态平衡的抑制在泡沫细胞的形成中起着关键作用，这是动脉粥样硬化发病机制的第一步。特别是，巨噬细胞中ABCA1/Abcg1表达减少导致胆固醇输出减少，从而导致泡沫细胞的形成。低水平的循环细菌内毒素脂多糖(LPS)持续存在于患有心血管并发症的人类中，并与巨噬细胞稳态的慢性改变有关。然而，其潜在的机制还不是很清楚。我们观察到，亚临床低度内毒素血症通过减少巨噬细胞中关键的胆固醇输出因子ABCA1/Abcg1的表达而有效地抑制巨噬细胞的胆固醇输出。在机制上，我们证明了低剂量的内毒素选择性地抑制核受体，包括RARA到SRC-3，通过IRAK-1和Tollip依赖的途径。当喂食高脂饮食时，IRAK-1缺失的小鼠可以减轻动脉粥样硬化斑块的形成。我们的长期目标是确定新的细胞内治疗靶点，用于治疗由 亚临床内毒素血症。本研究的目的是探讨亚临床低剂量内毒素抑制巨噬细胞ABCA1/Abcg1表达和胆固醇输出的分子机制。我们的假设是，亚临床内毒素血症选择性地在宿主巨噬细胞中建立了一个独特的细胞内信号网络，该网络优先抑制ABCA1/Abcg1的表达和胆固醇输出。为了检验这一假设，我们设计了以下具体目标。1)研究IRAK-1在小剂量脂多糖优先抑制巨噬细胞核受体和Abcg1/ABCA1表达过程中的作用和调节。具体地说，我们计划研究IRAK-1介导的调节SRC-3、ABCA1/Abcg1表达和低剂量内毒素处理的巨噬细胞胆固醇输出的机制。2)研究Tollip在小剂量脂多糖诱导巨噬细胞ABCA1/Abcg1表达和胆固醇排出中的作用。3)研究IRAK-1和Tollip在体内动脉粥样硬化发病机制中的作用。这个项目将对我们理解先天免疫和低度炎症，以及确定治疗动脉粥样硬化等慢性疾病的可行靶点产生很大影响。

DESCRIPTION (provided by applicant): Suppression of macrophage homeostasis plays a key role during the foam cell formation, an initial step toward the pathogenesis of atherosclerosis. In particular, reduced cholesterol export due to decreased ABCA1/ABCG1 expression in macrophages leads to the foam cell formation. Low levels of circulating bacterial endotoxin lipopolysaccharide (LPS) are persistently present in humans with cardiovascular complications, and are responsible for chronic alteration of macrophage homeostasis. However, the underlying mechanism is not well understood. We observed that subclinical low grade endotoxemia potently represses cholesterol export from macrophages through reducing the expression of ABCA1/ABCG1, key cholesterol exporters in macrophages. Mechanistically, we demonstrated that low dose LPS selectively represses nuclear receptors including RARa through SRC-3, in an IRAK-1 and Tollip dependent pathway. Mice with IRAK-1 deletion have alleviated formation of atherosclerotic plaques when fed with a high fat diet. Our long term goal is to define novel intracellular therapeutic targets for the treatment of atherosclerosis caused by subclinical endotoxemia. Our objective of this project is to determine molecular mechanisms by which subclinical low dose endotoxin represses the expression of ABCA1/ABCG1 and cholesterol export in macrophages. Our hypothesis is that subclinical endotoxemia selectively establishes a unique intracellular signaling network in host macrophages, which preferentially represses the expression of ABCA1/ABCG1 and cholesterol export. The following specific aims are designed to test this hypothesis. 1) The role and regulation of IRAK-1 during the preferential suppression of nuclear receptors and ABCG1/ABCA1 expression in macrophages by low dose LPS will be examined. Specifically, we plan to examine the mechanisms responsible for IRAK-1 mediated regulation of SRC-3, ABCA1/ABCG1 expression and cholesterol export in macrophages treated with a low dose LPS. 2) The role of Tollip in modulating ABCA1/ABCG1 expression and cholesterol export in macrophages by low dose LPS will be determined. 3) The role of IRAK-1 and Tollip during the pathogenesis of atherosclerosis in vivo will be examined. This project will have a high impact on our understanding of innate immunity and low grade inflammation, as well as on identification of viable therapeutic target for the treatment of chroni diseases such as atherosclerosis.