LPS Efflux from Host Cells to Plasma Lipoproteins

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DESCRIPTION (provided by applicant): 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.