Innate Modulation of Macrophage Homeostasis

巨噬细胞稳态的先天调节

• 批准号: 8852690
• 负责人: LIWU LI
• 金额: $ 39.3万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852690
• 关键词: ATP binding cassette transporter 1; Arterial Fatty Streak; Atherosclerosis; Binding; C2 Domain; Cardiovascular system; Cells; Cholesterol; Chronic; Clinical Research; Data; Development; Diet; Disease; Dose; Down-Regulation; Endotoxemia; Endotoxins; Fatty acid glycerol esters; Foam Cells; Future; Goals; Homeostasis; Human; Immune; Inflammation; Inflammatory; Laboratory Animals; Lipid Binding; Lipopolysaccharides; Mediating; Molecular; Molecular Target; Mus; Natural Immunity; Nuclear Receptors; Pathogenesis; Pathway interactions; Play; Process; Regulation; Role; Signal Transduction; Testing; Ubiquitin; Ubiquitination; Work; base; design; effective therapy; feeding; human IRAK1 protein; in vivo; insight; macrophage; novel; therapeutic target

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.

描述（由申请人提供）：巨噬细胞稳态的抑制在泡沫细胞形成过程中发挥关键作用，泡沫细胞形成是动脉粥样硬化发病机制的第一步。特别是，由于巨噬细胞中 ABCA1/ABCG1 表达减少而导致胆固醇输出减少，导致泡沫细胞形成。患有心血管并发症的人体内持续存在低水平的循环细菌内毒素脂多糖（LPS），并导致巨噬细胞稳态的慢性改变。然而，其基本机制尚不清楚。我们观察到，亚临床低度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。从机制上讲，我们证明低剂量 LPS 通过 SRC-3 在 IRAK-1 和 Tollip 依赖性途径中选择性抑制包括 RARa 在内的核受体。当喂食高脂肪饮食时，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，用于治疗由以下原因引起的动脉粥样硬化： 亚临床内毒素血症。我们该项目的目标是确定亚临床低剂量内毒素抑制巨噬细胞中 ABCA1/ABCG1 表达和胆固醇输出的分子机制。我们的假设是，亚临床内毒素血症在宿主巨噬细胞中选择性地建立独特的细胞内信号网络，优先抑制 ABCA1/ABCG1 的表达和胆固醇输出。以下具体目标旨在检验这一假设。 1)将检查IRAK-1在低剂量LPS​​优先抑制巨噬细胞中核受体和ABCG1/ABCA1表达过程中的作用和调节。具体来说，我们计划检查低剂量 LPS 处理的巨噬细胞中 IRAK-1 介导的 SRC-3、ABCA1/ABCG1 表达和胆固醇输出调节的机制。 2) 将确定 Tollip 在低剂量 LPS 调节巨噬细胞中 ABCA1/ABCG1 表达和胆固醇输出中的作用。 3) 研究IRAK-1和Tollip在体内动脉粥样硬化发病机制中的作用。该项目将对我们对先天免疫和低度炎症的理解，以及确定治疗动脉粥样硬化等慢性疾病的可行治疗靶点产生重大影响。