The stimulatory effects of bacterial lipopolysaccharide (LPS or endotoxin) can enhance beneficial innate immune responses in animal hosts, whereas its potential toxicity is thought to contribute importantly to the pathophysiology of sepsis. Plasma lipoproteins bind and neutralize LPS and help to control monocyte activation by promoting LPS efflux from these cells. In contrast to circulating monocytes, we found that differentiated macrophages can promote rapid LPS efflux without a requirement for any plasma constituent. ATP-binding cassette transporter A1 (ABCA1) and endogenously synthesized apolipoprotein E (apoE) can remove macrophage-associated LPS by mechanisms that are similar to those that remove inflammatory host lipids from macrophages and help reduce atherosclerosis. Since apoE is known to increase resistance to LPS toxicity and bacterial infection, we hypothesize that macrophage-derived apolipoproteins and ABC transporters help control local inflammation by decreasing LPS bioactivity and preventing LPS accumulation in tissues.
Our Specific Aims are to determine: (I) The molecular mechanisms of LPS efflux from macrophages, specifically the roles of ABCA1 and macrophage-derived apolipoproteins (apoE and apoC-l). (II) The disposition and bioactivity of the LPS that is released from macrophages, primarily in terms of its association with apoE and apoC-l. We will also study LPS-apoE interactions with apoE receptors. (Ill) The regulation of apolipoproteins and related genes during inflammation and sepsis in mice, and the effects of macrophage specific expression or deficiency of apoE in vivo to determine the impact of macrophage-derived apoE on local inflammation, innate immune responses, and resistance to bacterial infection. It is hoped that these studies will define novel mechanisms for the control of local inflammation by macrophages and apolipoproteins and that these studies will lead to improvements in the management of sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045896-07
Application #
7034603
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Sawyer, Richard T
Project Start
2000-04-01
Project End
2009-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
7
Fiscal Year
2006
Total Cost
$304,668
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Shao, Baomei; Munford, Robert S; Kitchens, Richard et al. (2012) Hepatic uptake and deacylation of the LPS in bloodborne LPS-lipoprotein complexes. Innate Immun 18:825-33
Thompson, Patricia A; Gauthier, Karine C; Varley, Alan W et al. (2010) ABCA1 promotes the efflux of bacterial LPS from macrophages and accelerates recovery from LPS-induced tolerance. J Lipid Res 51:2672-85
Li, Li; Thompson, Patricia A; Kitchens, Richard L (2008) Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors. J Lipid Res 49:1782-93
Thompson, Patricia A; Berbee, Jimmy F P; Rensen, Patrick C N et al. (2008) Apolipoprotein A-II augments monocyte responses to LPS by suppressing the inhibitory activity of LPS-binding protein. Innate Immun 14:365-74
Seetharam, Divya; Mineo, Chieko; Gormley, Andrew K et al. (2006) High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I. Circ Res 98:63-72
Thompson, Patricia A; Kitchens, Richard L (2006) Native high-density lipoprotein augments monocyte responses to lipopolysaccharide (LPS) by suppressing the inhibitory activity of LPS-binding protein. J Immunol 177:4880-7
Berbee, Jimmy F P; van der Hoogt, Caroline C; Kleemann, Robert et al. (2006) Apolipoprotein CI stimulates the response to lipopolysaccharide and reduces mortality in gram-negative sepsis. FASEB J 20:2162-4
Kitchens, Richard L; Thompson, Patricia A (2005) Modulatory effects of sCD14 and LBP on LPS-host cell interactions. J Endotoxin Res 11:225-9
Kitchens, Richard L; Thompson, Patricia A; Munford, Robert S et al. (2003) Acute inflammation and infection maintain circulating phospholipid levels and enhance lipopolysaccharide binding to plasma lipoproteins. J Lipid Res 44:2339-48
Thompson, Patricia A; Tobias, Peter S; Viriyakosol, Suganya et al. (2003) Lipopolysaccharide (LPS)-binding protein inhibits responses to cell-bound LPS. J Biol Chem 278:28367-71

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