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.
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.
|Lee, Christina; Geng, Shuo; Zhang, Yao et al. (2017) Programming and memory dynamics of innate leukocytes during tissue homeostasis and inflammation. J Leukoc Biol 102:719-726|
|Rothschild, Daniel E; Zhang, Yao; Diao, Na et al. (2017) Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M. EBioMedicine 15:36-47|
|Chen, Keqiang; Yuan, Ruoxi; Geng, Shuo et al. (2017) Toll-interacting protein deficiency promotes neurodegeneration via impeding autophagy completion in high-fat diet-fed ApoE-/- mouse model. Brain Behav Immun 59:200-210|
|Guo, Honghui; Diao, Na; Yuan, Ruoxi et al. (2016) Subclinical-Dose Endotoxin Sustains Low-Grade Inflammation and Exacerbates Steatohepatitis in High-Fat Diet-Fed Mice. J Immunol 196:2300-2308|
|Geng, Shuo; Chen, Keqiang; Yuan, Ruoxi et al. (2016) The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis. Nat Commun 7:13436|
|Yuan, Ruoxi; Li, Liwu (2016) Dynamic modulation of innate immunity programming and memory. Sci China Life Sci 59:38-43|
|Yuan, Ruoxi; Geng, Shuo; Chen, Keqiang et al. (2016) Low-grade inflammatory polarization of monocytes impairs wound healing. J Pathol 238:571-83|
|Lu, Geming; Zhang, Ruihua; Geng, Shuo et al. (2015) Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun 6:6676|
|Chen, Keqiang; Geng, Shuo; Yuan, Ruoxi et al. (2015) Super-low dose endotoxin pre-conditioning exacerbates sepsis mortality. EBioMedicine 2:324-333|
|Baker, Bianca; Geng, Shuo; Chen, Keqiang et al. (2015) Alteration of lysosome fusion and low-grade inflammation mediated by super-low-dose endotoxin. J Biol Chem 290:6670-8|
Showing the most recent 10 out of 17 publications