Innate Modulation of Macrophage Homeostasis

描述（由申请人提供）：抑制巨噬细胞稳态在泡沫细胞形成过程中起关键作用，泡沫细胞形成是动脉粥样硬化发病机制的初始步骤。特别是，由于巨噬细胞中ABCA 1/ABCG 1表达减少而导致胆固醇输出减少导致泡沫细胞形成。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，并且是导致巨噬细胞稳态慢性改变的原因。然而，其基本机制尚未得到很好的理解。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胆固醇输出者ABCA 1/ABCG 1的表达而有效地抑制巨噬细胞的胆固醇输出。从机制上讲，我们证明了低剂量LPS在IRAK-1和Tollip依赖性途径中通过SRC-3选择性地抑制包括RAR α在内的核受体。IRAK-1缺失的小鼠在喂食高脂饮食时减轻了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，用于治疗动脉粥样硬化， 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ABCA 1/ABCG 1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ABCA 1/ABCG 1的表达和胆固醇输出。以下具体目标旨在检验这一假设。1)IRAK-1在低剂量LPS优先抑制巨噬细胞核受体和ABCG 1/ABCA 1表达过程中的作用和调节将被检查。具体而言，我们计划研究IRAK-1介导的SRC-3，ABCA 1/ABCG 1表达和胆固醇输出在低剂量LPS处理的巨噬细胞中的调节机制。2)将确定Tollip在调节低剂量LPS引起的巨噬细胞中ABCA 1/ABCG 1表达和胆固醇输出中的作用。3)将检查IRAK-1和Tollip在体内动脉粥样硬化发病过程中的作用。该项目将对我们理解先天免疫和低度炎症以及确定治疗慢性疾病（如动脉粥样硬化）的可行治疗靶点产生重大影响。

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.