Crosstalk between reverse cholesterol transport and innate immunity

Abstract

Although lipid metabolism and host defense are widely considered to be very divergent disciplines, compelling evidence suggests that host cell handling of self- and microbe-derived (e.g. lipopolysaccharide, LPS) lipids may have common evolutionary roots, and that they indeed may be inseparable processes. The innate immune response and the homeostatic network controlling cellular sterol levels are now known to regulate each other reciprocally, with important implications for several common diseases, including atherosclerosis. In the present review we discuss recent discoveries that provide new insight into the bidirectional crosstalk between reverse cholesterol transport and innate immunity, and highlight the broader implications of these findings for the development of therapeutics.

Figure 1. LPS and cholesterol share common trafficking and disposal pathways

Removal of cholesterol from macrophage to gut, referred to as ‘reverse cholesterol transport’ and how LPS trafficking integrates into it, are depicted. LBP facilitates binding of bacterial LPS to CD14 on cell membranes or in plasma (sCD14). In addition to interactions with CD14/TLR4, LPS is taken up into cells via SR-BI. HDL can release cell-bound LPS, and sCD14 enhances this release, while ABCA1 promotes additional efflux of LPS, along with FC and PL. PLTP promotes the disaggregation of LPS, allowing its binding to HDL, thereby reducing LPS interaction with cells. Following remodeling of HDL by LCAT, CETP, and PLTP, HDL cargo, including CE and LPS, are taken up by the liver in an SR-BI-dependent fashion; LDL receptor-mediated uptake of cholesterol and perhaps LPS by liver from VLDL/LDL also occur. Cholesterol is metabolized by CYP7A1 into bile acids in the liver; free cholesterol, bile acids, and LPS are then transported into bile for elimination in the feces. A less characterized, alternate pathway for direct elimination of serum cholesterol into the intestinal lumen, called ‘transintestinal cholesterol efflux’ (TICE), is also shown. Proteins negatively regulated by inflammation include ABC-A1/-G1/-G5/-G8, SR-BI, apoA-I, LCAT, CETP, and CYP7A1. ABC, ATP Binding Cassette; CE, cholesteryl ester; CETP, CE transfer protein; FC, free cholesterol, HDL, high density lipoprotein; LBP, LPS binding protein; LCAT, lecithin:cholesterol acyltransferase; LDL, low density lipoprotein; LPS, lipopolysaccharide; LXR, liver X receptor; PLTP, phospholipid transfer protein; RXR, retinoid X receptor; SR-BI, scavenger receptor class B type I; VLDL, very low density lipoprotein.

Figure 2. Sites of interaction between RCT and TLRs in the macrophage

ABCA1 null macrophages have an enhanced pro-inflammatory response to ligands for TLR2, TLR4, TLR7, and TLR9 compared with wt macrophages, likely reflecting increased cholesterol and TLR assembly in lipid rafts. ABCG1 null macrophages have a similar TLR-hyperresponsive phenotype. Conversely, apoA-I suppresses cytokine induction through an ABCA1-activated JAK2-STAT3 pathway and perhaps also through disrupting rafts, while HDL suppresses the type I interferon response pathway downstream of TLR4, by promoting translocation of the TLR adaptor TRAM to intracellular compartments. SR-BI also suppresses TLR4-mediated NF-κB activation. Pathogens in turn interfere with LXR signaling by stimulating TLR3/4-dependent activation of IRF-3, which is thought to interact with the LXRE on LXR target genes, such ABCA1 and ABCG1. HDL and apoA-I can also activate the ectodomain shedding of ADAM17 substrates, such as TNFR2, TNFR1, and TNFα, leading to their release. ABC, ATP binding cassette; Adam, a disintegrin and metalloproteinase; HDL, high density lipoprotein; IRF, interferon regulatory factor; Jak, Janus kinase; LXR, Liver X Receptor; SR-BI, scavenger receptor class B type I; Stat3, signal transducer and activator of transcription; TLR, Toll like Receptor; TNFR, tumor necrosis factor receptor.