Innate Modulation of Macrophage Homeostasis

描述（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，导致泡沫细胞形成。低水平的循环细菌内毒素脂多糖（LPS）持续存在于心血管并发症患者中，并导致巨噬细胞稳态的慢性改变。然而，其潜在机制尚不清楚。我们观察到亚临床低级别内毒素血症通过降低巨噬细胞中关键胆固醇输出蛋白ABCA1/ABCG1的表达，有效抑制巨噬细胞的胆固醇输出。在机制上，我们证明了低剂量LPS通过SRC-3选择性地抑制包括RARa在内的核受体，通过IRAK-1和Tollip依赖途径。IRAK-1缺失的小鼠在喂食高脂肪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来治疗动脉粥样硬化

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.