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.

Public Health Relevance

Altered macrophage homeostasis under low grade inflammatory conditions underlies the initiation and progression of chronic inflammatory diseases such as atherosclerosis. The goal of this project is to define the mechanisms responsible for the suppression of cholesterol export from innate immune macrophages. The role of a novel adaptor molecule Tollip during this key process will be examined and revealed. This project will provide novel insight into low grade inflammation, and also reveal potential molecular target for the treatment of chronic inflammatory diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL115835-03
Application #
8686071
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Blacksburg
State
VA
Country
United States
Zip Code
24060
Baker, Bianca; Maitra, Urmila; Geng, Shuo et al. (2014) Molecular and cellular mechanisms responsible for cellular stress and low-grade inflammation induced by a super-low dose of endotoxin. J Biol Chem 289:16262-9
Morris, Matthew C; Gilliam, Elizabeth A; Button, Julia et al. (2014) Dynamic modulation of innate immune response by varying dosages of lipopolysaccharide (LPS) in human monocytic cells. J Biol Chem 289:21584-90
Deng, Hui; Maitra, Urmila; Morris, Matt et al. (2013) Molecular mechanism responsible for the priming of macrophage activation. J Biol Chem 288:3897-906
Maitra, Urmila; Li, Liwu (2013) Molecular mechanisms responsible for the reduced expression of cholesterol transporters from macrophages by low-dose endotoxin. Arterioscler Thromb Vasc Biol 33:24-33