Review
Anti-atherogenic mechanisms of high density lipoprotein: Effects on myeloid cells

https://doi.org/10.1016/j.bbalip.2011.08.003Get rights and content

Abstract

In some settings increasing high density lipoprotein (HDL) levels has been associated with a reduction in experimental atherosclerosis. This has been most clearly seen in apolipoprotein A-I (apoA-I) transgenic mice or in animals infused with HDL or its apolipoproteins. A major mechanism by which these treatments are thought to delay progression or cause regression of atherosclerosis is by promoting efflux of cholesterol from macrophage foam cells. In addition, HDL has been described as having anti-inflammatory and other beneficial effects. Some recent research has linked anti-inflammatory effects to cholesterol efflux pathways but likely multiple mechanisms are involved. Macrophage cholesterol efflux may have a role in facilitating emigration of macrophages from lesions during regression. While macrophages can mediate cholesterol efflux by several pathways, studies in knockout mice or cells point to the importance of active efflux mediated by ATP binding cassette transporter (ABC) A1 and G1. In addition to traditional roles in macrophages, these transporters have been implicated in the control of hematopoietic stem cell proliferation, monocytosis and neutrophilia, as well as activation of monocytes and neutrophils. Thus, HDL and cholesterol efflux pathways may have important anti-atherogenic effects at all stages of the myeloid cell/monocyte/dendritic cell/macrophage lifecycle. 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).

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)

  • W. Diederich et al.

    Apolipoprotein AI and HDL(3) inhibit spreading of primary human monocytes through a mechanism that involves cholesterol depletion and regulation of CDC42

    Atherosclerosis

    (2001)
  • O. Soehnlein

    An elegant defense: how neutrophils shape the immune response

    Trends Immunol.

    (2009)
  • P. Rotzius et al.

    Distinct infiltration of neutrophils in lesion shoulders in ApoE/ mice

    Am. J. Pathol.

    (2010)
  • F.B. Araujo et al.

    Evaluation of oxidative stress in patients with hyperlipidemia

    Atherosclerosis

    (1995)
  • R. Mazor et al.

    Primed polymorphonuclear leukocytes constitute a possible link between inflammation and oxidative stress in hyperlipidemic patients

    Atherosclerosis

    (2008)
  • O. Soehnlein et al.

    Mechanisms underlying neutrophil-mediated monocyte recruitment

    Blood

    (2009)
  • L.M. Pierini et al.

    Membrane lipid organization is critical for human neutrophil polarization

    J. Biol. Chem.

    (2003)
  • D. Shao et al.

    Lipid rafts determine efficiency of NADPH oxidase activation in neutrophils

    FEBS Lett.

    (2003)
  • A.R. Tall et al.

    HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis

    Cell Metab.

    (2008)
  • X. Zhu et al.

    Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol

    J. Lipid Res.

    (2010)
  • C.T. Park et al.

    Plasma lipopolysaccharide-binding protein is found associated with a particle containing apolipoprotein A-I, phospholipid, and factor H-related proteins

    J. Biol. Chem.

    (1996)
  • R.L. Kitchens et al.

    Plasma lipoproteins promote the release of bacterial lipopolysaccharide from the monocyte cell surface

    J. Biol. Chem.

    (1999)
  • R. Patino et al.

    Circulating monocytes in patients with diabetes mellitus, arterial disease, and increased CD14 expression

    Am. J. Cardiol.

    (2000)
  • H. Kamata et al.

    Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases

    Cell

    (2005)
  • C. Tang et al.

    The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor

    J. Biol. Chem.

    (2009)
  • A.M. Vaughan et al.

    ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation

    J. Lipid Res.

    (2009)
  • L.M. Williams et al.

    Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages

    J. Biol. Chem.

    (2007)
  • K. Yin et al.

    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.

    (2011)
  • K.J. Williams et al.

    The response-to-retention hypothesis of early atherogenesis

    Arterioscler. Thromb. Vasc. Biol.

    (1995)
  • K.J. Williams et al.

    The response-to-retention hypothesis of atherogenesis reinforced

    Curr. Opin. Lipidol.

    (1998)
  • C.R. Stewart et al.

    CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer

    Nat. Immunol.

    (2010)
  • N. Terasaka et al.

    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.

    (2007)
  • L. Yvan-Charvet et al.

    ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis

    Circ. Res.

    (2010)
  • L. Yvan-Charvet et al.

    Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice

    J. Clin. Invest.

    (2007)
  • A.J. Murphy et al.

    The anti inflammatory effects of high density lipoproteins

    Curr. Med. Chem.

    (2009)
  • A.J. Murphy et al.

    High-density lipoprotein: a potent inhibitor of inflammation

    Clin. Exp. Pharmacol. Physiol.

    (2010)
  • L. Yvan-Charvet et al.

    ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation

    Science

    (2010)
  • G.A. Francis et al.

    Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier disease

    J. Clin. Invest.

    (1995)
  • M. Bodzioch et al.

    The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease

    Nat. Genet.

    (1999)
  • A. Brooks-Wilson et al.

    Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency

    Nat. Genet.

    (1999)
  • R.M. Lawn et al.

    The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway

    J. Clin. Invest.

    (1999)
  • A.T. Remaley et al.

    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.

    (1999)
  • S. Rust et al.

    Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1

    Nat. Genet.

    (1999)
  • N. Wang et al.

    ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • S.H. Najafi-Shoushtari et al.

    MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis

    Science

    (2010)
  • K.J. Rayner et al.

    MiR-33 contributes to the regulation of cholesterol homeostasis

    Science

    (2010)
  • V. Brinkmann et al.

    Neutrophil extracellular traps kill bacteria

    Science

    (2004)
  • T. Horie et al.

    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.

    (2010)
  • T.J. Marquart et al.

    miR-33 links SREBP-2 induction to repression of sterol transporters

    Proc. Natl. Acad. Sci. U.S.A.

    (2010)
  • E.P. de Grouw et al.

    Preferential expression of a high number of ATP binding cassette transporters in both normal and leukemic CD34 + CD38− cells

    Leukemia

    (2006)
  • Cited by (0)

    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).

    View full text