Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewAnti-atherogenic mechanisms of high density lipoprotein: Effects on myeloid cells☆
Highlights
► HDL can regulate myelopoiesis through ABCA1 and ABCG1. ► HDL can prevent monocyte entry into the atherosclerotic lesion by inhibiting number and activation. ► HDL attenuates neutrophil activation and adhesion in acute models of inflammation. ► HDL modulates macrophage functions including migration, efferocytosis and TLR signaling.
Introduction
Atherosclerosis is an indolent, macrophage dominated, focal inflammatory disease of the large arteries. This process is initiated by the deposition of ApoB containing lipoproteins on the arterial proteoglycan matrix in regions of disturbed blood flow, followed by their modification and uptake by macrophages [1], [2]. Modified lipoproteins also activate combinatorial signaling by toll like receptors (TLR) and scavenger receptors (SR) on macrophages, and the effects of lipid loading and TLR/SR signaling lead to inflammatory and chemokine responses, ER stress, apoptosis and necrosis [3], [4], [5]. These latter events are thought to lead to the ultimate complications of plaque rupture and athero-thrombosis. Although traditionally viewed as having a key role in removing the mass of cholesterol from plaques in a process of reverse cholesterol transport, HDL is now seen as having key effects on macrophage inflammation, ER stress and apoptosis (Fig. 1). Some of these effects are dependent on the fundamental ability of HDL and apoA-I to interact with the ATP binding cassette transporters on macrophages, ABCA1 and ABCG1, mediating efflux of cholesterol and oxidized lipids [6], [7], [8], but likely multiple mechanisms are involved. Recent studies also point to a role of HDL, ABCA1, ABCG1 in controlling monocyte activation, adhesiveness and inflammation [9], [10], and in controlling the proliferation of the stem and progenitor cells [11] that give rise to monocytes and neutrophils that ultimately enter plaques.
Section snippets
ABCA1 and ABCG1 are key mediators of cholesterol efflux
Francis and Oram made the seminal discovery that fibroblasts isolated from Tangier Disease (TD) subjects could not promote the efflux of cholesterol or phospholipids to lipid-free apoA-I [12], [13]. Several groups discovered through the use of micro-arrays, genetic mapping and biochemical assays that Abca1 was the defective gene in Tangier Disease [14], [15], [16], [17], [18]. Through this discovery and using techniques to specifically knockdown the expression of Abca1 it was then demonstrated
HDL, ApoE, ABCA1 and ABCG1 regulate myelopoiesis and monocyte numbers
Hematopoiesis is hierarchical and ordered, and is initiated by long term self-renewing and multi-potent stem cells. Through a process of proliferation, lineage restriction and differentiation, HSPCs give rise to mature lineage committed cells, that ultimately form the mature blood cells. Production of blood cells in the steady state is tightly regulated by a number of well-defined feedback loops. However, production can be increased when required, for instance in response to infection or blood
Anti-inflammatory effects of HDL in the innate immune response
In this review we have set out to detail the anti-atherosclerotic effects on myeloid cells. However it is of importance to note that in the setting of atherosclerosis and vascular inflammation HDL also acts on the endothelial cells, the cells to which monocytes adhere to and use to migrate through to the atherosclerotic lesion. HDL plays a role in regulating vascular tone by stimulating endothelial cells to release nitric oxide (NO) by activating endothelial nitric oxide synthase (eNOS) when it
Conclusions and future directions
There appears to be a discordance between the relative lack of success of HDL raising strategies in the clinic, and the plethora of beneficial actions of HDL that have been demonstrated in cell culture and animal models. It is clear that not all strategies for raising HDL are likely to be beneficial. There is a need for more critical evaluation of the different proposed functionalities of HDL, as outlined here and elsewhere [101], [102], [103], [104] both in animal models and in the clinic. Our
References (106)
- et al.
Macrophages in the pathogenesis of atherosclerosis
Cell
(2011) - et al.
Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress
Cell Metab.
(2010) - et al.
Reduction in apolipoprotein-mediated removal of cellular lipids by immortalization of human fibroblasts and its reversion by cAMP: lack of effect with Tangier disease cells
J. Lipid Res.
(1999) - et al.
ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation
Cell Metab.
(2005) - et al.
Selective expression of cholesterol metabolism genes in normal CD34 + CD38− cells with a heterogeneous expression pattern in AML cells
Exp. Hematol.
(2006) - et al.
Hypercholesterolemia promotes bone marrow cell mobilization by perturbing the SDF-1:CXCR4 axis
Blood
(2010) - et al.
LXR signaling couples sterol metabolism to proliferation in the acquired immune response
Cell
(2008) - et al.
Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr−/−, ApoA-I−/− mice
J. Biol. Chem.
(2010) - et al.
Low dose apolipoprotein A-I rescues carotid arteries from inflammation in vivo
Atherosclerosis
(2008) - et al.
Reconstituted high-density lipoprotein increases plasma high-density lipoprotein anti-inflammatory properties and cholesterol efflux capacity in patients with type 2 diabetes
J. Am. Coll. Cardiol.
(2009)
Apolipoprotein AI and HDL(3) inhibit spreading of primary human monocytes through a mechanism that involves cholesterol depletion and regulation of CDC42
Atherosclerosis
An elegant defense: how neutrophils shape the immune response
Trends Immunol.
Distinct infiltration of neutrophils in lesion shoulders in ApoE−/− mice
Am. J. Pathol.
Evaluation of oxidative stress in patients with hyperlipidemia
Atherosclerosis
Primed polymorphonuclear leukocytes constitute a possible link between inflammation and oxidative stress in hyperlipidemic patients
Atherosclerosis
Mechanisms underlying neutrophil-mediated monocyte recruitment
Blood
Membrane lipid organization is critical for human neutrophil polarization
J. Biol. Chem.
Lipid rafts determine efficiency of NADPH oxidase activation in neutrophils
FEBS Lett.
HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis
Cell Metab.
Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol
J. Lipid Res.
Plasma lipopolysaccharide-binding protein is found associated with a particle containing apolipoprotein A-I, phospholipid, and factor H-related proteins
J. Biol. Chem.
Plasma lipoproteins promote the release of bacterial lipopolysaccharide from the monocyte cell surface
J. Biol. Chem.
Circulating monocytes in patients with diabetes mellitus, arterial disease, and increased CD14 expression
Am. J. Cardiol.
Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases
Cell
The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor
J. Biol. Chem.
ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation
J. Lipid Res.
Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages
J. Biol. Chem.
Tristetraprolin-dependent Post-transcriptional Regulation of Inflammatory Cytokine mRNA Expression by Apolipoprotein A-I: role of ATP-binding membrane cassette transporter A1 and signal transducer and activator of transcription 3
J. Biol. Chem.
The response-to-retention hypothesis of early atherogenesis
Arterioscler. Thromb. Vasc. Biol.
The response-to-retention hypothesis of atherogenesis reinforced
Curr. Opin. Lipidol.
CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer
Nat. Immunol.
High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1
Proc. Natl. Acad. Sci. U.S.A.
ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis
Circ. Res.
Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice
J. Clin. Invest.
The anti inflammatory effects of high density lipoproteins
Curr. Med. Chem.
High-density lipoprotein: a potent inhibitor of inflammation
Clin. Exp. Pharmacol. Physiol.
ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation
Science
Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier disease
J. Clin. Invest.
The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease
Nat. Genet.
Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency
Nat. Genet.
The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway
J. Clin. Invest.
Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred
Proc. Natl. Acad. Sci. U.S.A.
Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1
Nat. Genet.
ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins
Proc. Natl. Acad. Sci. U.S.A.
MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis
Science
MiR-33 contributes to the regulation of cholesterol homeostasis
Science
Neutrophil extracellular traps kill bacteria
Science
MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo
Proc. Natl. Acad. Sci. U.S.A.
miR-33 links SREBP-2 induction to repression of sterol transporters
Proc. Natl. Acad. Sci. U.S.A.
Preferential expression of a high number of ATP binding cassette transporters in both normal and leukemic CD34 + CD38− cells
Leukemia
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This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).