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ISSN: 2155-9899
Journal of Clinical & Cellular Immunology
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The Bidirectional Relationship between Cholesterol and Macrophage Polarization

Heather J Medbury1*, Helen Williams1, Stephen Li2 and John P Fletcher1
1Vascular Biology Research Centre, Department of Surgery, University of Sydney, Westmead Hospital, Westmead, NSW, Australia
2Clinical Chemistry, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia
Corresponding Author : Heather J Medbury
Vascular Biology Research Centre
Department of Surgery, University of Sydney
Westmead Hospital, Westmead, NSW, Australia
Tel: +61-2-9845-7677
Fax: +61-2-9893-7440
E-mail: [email protected]
Received January 09, 2015; Accepted February 26, 2015; Published February 28, 2015
Citation: Medbury HJ, Williams H, Li S, Fletcher JP (2015) The Bidirectional Relationship between Cholesterol and Macrophage Polarization. J Clin Cell Immunol 6:303. doi:10.4172/2155-9899.1000303
Copyright: © 2015 Medbury HJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Whether an atherosclerotic plaque progresses and eventually ruptures is heavily influenced by the function of macrophages. However, it is clear that a spectrum of macrophage phenotypes is present in the plaque, with some exhibiting stabilizing functions. While macrophages expressing characteristic M1 and M2 markers are evident, the disparate microenvironments of the plaque, such as regions of hemorrhage, promote other distinct macrophage phenotypes. Crucial to plaque development and progression is macrophage exposure to accumulated modified low density lipoproteins that leads to foam cell formation and development of the necrotic core. There are a range of biologically active compounds in low density lipoprotein (LDL) each having some bearing on which macrophage surface receptors are engaged and what cellular response ensues. Understanding the bidirectional interplay between ‘cholesterol’ and macrophage phenotype will provide valuable insight into key pathways to target which may possibly promote plaque stability by modulating macrophage function.

Abstract

Whether an atherosclerotic plaque progresses and eventually ruptures is heavily influenced by the function of macrophages. However, it is clear that a spectrum of macrophage phenotypes is present in the plaque, with some exhibiting stabilizing functions. While macrophages expressing characteristic M1 and M2 markers are evident, the disparate microenvironments of the plaque, such as regions of hemorrhage, promote other distinct macrophage phenotypes. Crucial to plaque development and progression is macrophage exposure to accumulated modified low density lipoproteins that leads to foam cell formation and development of the necrotic core. There are a range of biologically active compounds in low density lipoprotein (LDL) each having some bearing on which macrophage surface receptors are engaged and what cellular response ensues. Understanding the bidirectional interplay between ‘cholesterol’ and macrophage phenotype will provide valuable insight into key pathways to target which may possibly promote plaque stability by modulating macrophage function.
Keywords

Macrophage; Polarization; Cholesterol; Atherosclerosis; Review
Abbreviations

IL: Interleukin; iNOS: Inducible Nitric Oxide Synthase; IPH: Intra Plaque Haemorrhage; KLF: Krüppel Like Factor; LDL: Low Density Lipoprotein; LPS: Lipopolysaccharide; LXR: Liver X Receptor; M1: Type 1 Macrophage; M2: Type 2 Macrophage; M4: CXCL4 Derived Macrophage; M-Mac: M-CSF Derived Macrophage; MCP-1: Monocyte Chemotactic Protein 1; M-CSF: Macrophage Colony Stimulating Factor; MERTK: MER proto-oncogene, Tyrosine Kinase; Mhem: Heme Directed Macrophage; MIP-2: Macrophage Inflammatory Protein-2; mmLDL: Minimally Modified Oxidized LDL; Mox: Oxidised Phospholipid Derived Macrophages; MR: Mannose Receptor; NLRP3: NLR Family, Pyrin Domain containing 3; Nrf2: Nuclear Factor (erythroid-derived 2)-like 2; oxLDL: Oxidised LDL; PPARγ: Peroxisome Proliferator-Activated Receptor Gamma; STAT: Signal Transducer and Activator of Transcription; TNF: Tumour Necrosis Factor
Introduction

Macrophages are a major cell type in the atherosclerotic plaque which play a key role in plaque development, progression and ultimately, rupture. An early and ongoing process in plaque development is macrophage uptake of modified LDL (a major carrier of cholesterol) that has accumulated in the sub-endothelial space [1,2]. This ingestion of retained lipoprotein transforms the macrophages into foam cells [3] and an inflammatory response ensues. However, this response is maladapted as the macrophage foam cells do not leave but are retained within the vessel wall [2]. Foam cell accumulation, their apoptosis and subsequent necrosis leads to development of the necrotic core - a major contributor to plaque instability [4,5]. It is thus important to understand the processes involved in, and outcome of, macrophage lipoprotein uptake. This review will cover lipoprotein uptake by the different macrophage phenotypes identified in the plaque and, in addition, as cholesterol uptake or efflux can further modify macrophage function, the effect of LDL and HDL on macrophage polarization is also discussed.
Macrophage phenotypes in the atherosclerotic plaque

While macrophage polarization suggests two extremes of phenotype, and indeed the terms M1 and M2 predominate in the literature, it is well appreciated that there is a spectrum of macrophage phenotypes that can be adopted with considerable plasticity between them [6]. This is especially apparent in atherosclerosis where monocytes, and subsequently macrophages, are exposed to an array of factors throughout plaque initiation and progression and in the advanced plaque. Monocyte differentiation into macrophages is promoted by growth and survival factors, including M-CSF, GM-CSF [7] and CXCL4 [8], with all three of these factors present in atherosclerotic plaques [9-11]. Factors such as IFN-γ, IL-4 and IL-10, which are known to promote M1 and M2 macrophage polarization [12] are also evident in the plaque [13,14] and, as such, macrophages expressing a range of M1 and M2 markers have been identified in both murine and human plaques [15-19]. Furthermore, the advanced plaque is complex and heterogeneous in nature, often containing regions of intra-plaque hemorrhage (IPH). A unique phenotype of macrophage, the Mhem (M(Hb) or HA-Mac) macrophage, forms in these regions [20-22]. Aside from these identified forms, a range of intermediate phenotypes may also be present. In addition, other monocyte-derived cells (which share overlapping functions with macrophages) are also present in the plaque, such as dendritic cells [23,24] and fibrocytes [25].

These various ‘polarized’ macrophage forms differ greatly in their ability to take up oxLDL. However, oxLDL uptake itself can also alter macrophage phenotype. The numerous bioactive compounds present in LDL, and their modified forms, exert specific effects. Oxidized phospholipids, for example, promote formation of the Mox macrophage, which is distinct from the M1 and M2 macrophage forms [26]. Cholesterol is also present in the plaque in crystalline form. Cholesterol crystals activate different and distinct pathways in the macrophages. Aside from cholesterol uptake, its efflux also influences macrophage phenotype, with emerging studies addressing how HDL may impact on the M1/M2 nature of macrophages in the plaque.
Effect of Macrophage Phenotype on ‘Cholesterol’ Uptake

M-Macs/GM-Macs and the M4 macrophage

Monocyte to macrophage differentiation is promoted by exposure of monocytes to macrophage colony stimulating factor (M-CSF), granulocyte macrophage colony stimulating factor (GM-CSF) or CXCL4 [7,8] and the macrophages formed have been described as M-Mac, GM-Mac [27] and M4 [28], respectively. It should be noted, however, that GM-CSF and M-CSF cultured macrophages have also been called M1 or M2 [29], but such designation is not recommended in the current nomenclature guidelines [30]. It is noted, though, that M-CSF stimulation induces expression of a substantial portion of the M2 transcriptome [31]. Furthermore, M-CSF differentiated macrophages have also been called M0 or resting macrophages [32]. In vitro, upon LPS stimulation, GM-CSF derived macrophages produce higher levels of inflammatory cytokines than their M-CSF derived counterparts [29,33]. Furthermore, M-CSF derived macrophages express higher levels of the M2 marker CD163 and the anti-inflammatory factor Krüppel-like factor (KLF)2 [29]. Though the GM-CSF derived macrophages are more inflammatory in nature [33], they accumulate less oxLDL than the M-CSF derived macrophages [29]. This may be attributed to M-CSF upregulation of CD36 [29], a receptor for oxLDL [34,35]. Conversely, GM-CSF has been found to upregulate expression of genes that promote reverse cholesterol transport (PPARγ, LXR-α and ABCG1 [27]). M-Macs retain CD14, while this is down-regulated in GM-Macs, which exclusively express 25F9 [27]. In human coronary atherosclerotic plaques, CD68+ macrophages staining both with, and without, CD14 are evident with CD14+ CD68+ macrophages prevalent in the lesion, whereas the CD14- CD68+ macrophages were found in areas devoid of disease [27].

CXCL4 derived macrophages (M4) lack CD163. Indeed, macrophages lacking CD163 are evident in the plaque [16], though these could also be M1 macrophages. The suppression of CD163 by CXCL4 could not be recovered by subsequent incubation with M-CSF or IL-10. Furthermore, the loss of CD163 was accompanied by an inability of hemoglobin-haptoglobin (Hb:Hp) to induce hemoxygenase 1 (HO-1) expression [16]. Transcriptome analysis and functional studies show that M4 macrophages are distinct from M-CSF differentiated as well as M1 and M2 polarized macrophages [36]. CD36 expression is lower on M4 macrophages than M-CSF differentiated macrophages and, accordingly, they have less intracellular cholesterol upon incubation with oxLDL [36]. The increased ABCG1 gene expression suggests that this may be through both reduced lipid uptake and increased efflux [36]. It is not clear whether M4 macrophages are predominantly pro- or anti-atherogenic [36]. However, as CXCL4 deficiency results in decreased atherosclerotic plaque burden [37], M4 macrophages may play a pro-atherosclerotic role [16].
M1 and M2 macrophages

After macrophage differentiation, exposure to cytokines such as IFN-γ and IL-4 primes the cells to adopt classical (M1) and alternative (M2) phenotypes, respectively [12]. The NF-κB pathway and signal transducer and activator of transcription (STAT) 1 direct M1 polarization [38-40], while the transcription factors Krüppel-like factor , peroxisome proliferator activated receptor-γ (PPARγ) and STAT6 [38-40] drive M2a macrophages. Exposure to IL-10 promotes M2c macrophages through STAT3 [41].

The lipid handling capacities of the M1 and M2 macrophages have been examined in vitro and the presence of M1 and M2 foam cells examined in both mouse and human plaques. Though M2a macrophages take up less lipid than resting macrophages [18], when M2a (IL-4), M2b(IC) and M2c (IL-10) were compared with M1 macrophages (M-CSF with LPS plus IFN-γ) they were found to take up more lipid [42]. (Although it is noted that monocytes in this later study were from obese subjects with diabetes). That said, IL-4, IL-10 and immunocomplex upregulate expression of CD36 and SR-A1 relative to IFN-γ [42] and separately, IFN-γ has been shown to reduce CD36 expression [43] which is consistent with the greater lipid uptake by M2, compared to M1, macrophages. As M2 (a,b and c) macrophages do not differ in apolipoprotein A1 (ApoA1) or HDL-stimulated cholesterol efflux compared with M1 macrophages (M-CSF with LPS plus IFN-γ), then the net increase in foam cell formation may primarily be due to cholesterol uptake [42]. However, in healthy controls, ApoA1- and HDL3-cholesterol efflux was found to be lower in M2a compared to resting macrophages [18]. Furthermore, the level of expression of both the ABCA1 and ApoE genes was lower in M2a compared to M1 and resting macrophages [18], suggesting that lower cholesterol efflux does contribute to increased cholesterol accumulation in M2 macrophages. Consistent with this increased lipid uptake, mannose receptor (MR: an M2 marker) positive macrophages were found localized more centrally within the plaque, in the ApoE-/- mouse, compared to M1 macrophages, and they exhibited a higher level of ADRP (a marker of lipid uptake) expression [42].

In human plaques, although the presence of inflammatory macrophages has long been recognized, the first identification of M2 macrophages was by Bouhlel in 2007 [15]. In contrast to the murine model, human M2 macrophages (MR+) have been found to be present in more stable regions of the plaque distant from the core [15,18]. MR+ foam cells that did form were reported to contain smaller lipid droplets than M1 foam cells [18] and, as such, foam cells are thought to primarily be M1 derived [18]. Of note, we have found that expression of the M2 markers MR (also known as CD206) and CD163 differs in carotid plaques, with many sections lacking MR but containing CD163 and then at a level comparable to that of the M1 markers, CD64 and CD86 [19]. Furthermore, when the M2 markers (CD163, MR) were present they, not just M1 (CD64 and CD86) markers, could be found on foam cells associated with the core. In addition, both M1 and M2 markers were found in the cap, primarily on spindle shaped cells [19].

The discrepancies between the murine and human data may reflect a difference in the stage of atherosclerosis examined, for although M2 foam cells have been found to predominate in young ApoE-/- mice, M1 foam cells are more prevalent in older mice [17]. Whether M2 macrophages and their foam cell forms predominate in the early human atherosclerotic plaque is not clear, but with M-CSF promoting expression of M2 related genes [31], then M2 macrophages (and subsequently M2 derived foam cells) may arise early in plaque development. Cholesterol uptake promotes ER stress which triggers the unfolded protein response [42,44]. Since M2 (IL-13 derived) foam cells are more sensitive to the unfolded protein response than other forms of macrophages [45], the lack of M2 macrophages in advanced human plaque may, in part, stem from increased cell death. Furthermore, during plaque progression the switch from an M2 to an M1 promoting environment may both impede apoptotic cell clearance (as M2 cells have greater capacity for efferocytosis) [46] and promote the formation of M1 macrophages/foam cells.

M1 macrophages are thought to be detrimental to plaque stability as aside from contributing to formation of the necrotic core, they contribute to thinning of the fibrous cap. M1 macrophages are found in the rupture-prone shoulder regions of the plaque [47] and there is an inverse relationship between the level of M1 (CD86), but not M2 (CD163), with carotid plaque cap thickness [19]. Similarly, levels of CD68 and CD11c (M1) are higher, while levels of the M2 markers (CD163 and MR) are lower in symptomatic patients compared to asymptomatic patients [48]. These findings are consistent with known role of M1 macrophages in tissue destruction [6]. M2 macrophages are considered athero-protective as they (CD163+ and CD206+ macrophages) produce collagen I in the carotid plaque [19]. This is consistent with their known role in tissue repair.
Mhem macrophages

Intraplaque hemorrhage is a common feature in the advanced plaque and its presence is associated with plaque progression [49]. Red blood cells have cholesterol enriched membranes which can result in increased cholesterol deposition and subsequent enlargement of the core [50]. Furthermore, RBC lysis releases hemoglobin. Heme and hemoglobin are strong oxidizers which could potentially increase lipid oxidation [51]. Hemoglobin is bound by haptoglobin to form the Hb:Hp complex [52] and macrophages scavenge this complex through CD163-the Hb:Hp receptor [52]. This results in the release of IL-10, which forms an autocrine loop, stimulating further expression of CD163 [22]. Such IPH localized macrophages are known as Mhem macrophages [20]). They are CD68posCD163highHLADRlow and thus distinct from conventional macrophage foam cells which are CD68posCD163lowHLADRhigh [22]. In vitro studies show that Hb:Hp driven adoption of the Mhem phenotype is IL-10 dependent [22] which suggests that the Mhem macrophages are related to the M2c form. While transcriptome analysis shows that Mhem are distinguishable from M2 (and M1) macrophages by the expression of ATF [20], this comparison was made between IL-4 stimulated (M2a) but not IL-10 stimulated macrophages. However, exposure to Hb:Hp (or heme [53]) will no doubt trigger upregulation of specific genes which would allow distinction of these cells from M2c macrophages.

Despite iron loading (as seen by the presence of CD163/Perls double stained cells in the plaque), the Mhem macrophages were negative for 8oxoG, a marker of oxidant stress, rather they stained strongly for HO-1 [22]. HO-1 breaks down hemoglobin to carbon monoxide, biliverdin (which is rapidly converted to bilirubin) and free iron [54] which is either used by the cell or bound by ferritin and exported out of the cell via the iron exporter ferroportin [21]. ATF-1 induced upregulation of HO-1 enables the safe handling of iron. At the same time, ATF-1 also promotes iron cholesterol efflux through a LXRβ → LXRα → ABCA1 pathway [20]. As such, Mhem macrophages are resistant to lipid loading as they have lower expression of genes associated with lipid uptake, but higher expression of genes involved in reverse cholesterol transport [20,21]. In the plaque, Mhem macrophages are found distant from the core and do not take up lipid [20-22]. Indeed, CD163+ macrophages are reported to be absent from lesions that have a lipid core but no hemorrhage [22].

The anti-inflammatory functions of the Mhem form are athero-protective. Their occurrence in IPH, which is associated with plaque progression, is thought to be a case of an adaptive response which is ‘too little too late’ [55]. Moreover, formation of the full Mhem state may be inhibited in the plaque as IFN-γ and LPS can prevent Mhem formation [22]. Furthermore, it has been shown in thrombi from acute coronary syndrome (ACS) patients, with diabetes or insulin resistance, that IL-10 production is impaired. This would further limit the ability of the Mhem to stabilize the plaque [56].
Effect of ‘Cholesterol’ on Macrophage Polarization

While variation in lipid handling by different macrophage phenotypes is evident, the reverse is also apparent, that lipid handling alters macrophage polarization. LDL is the major carrier of cholesterol, and its modification and uptake by macrophages leads to foam cell formation in the atherosclerotic plaque. Efflux of cholesterol from macrophages, i.e. reverse cholesterol transport, is mediated by HDL or its apolipoproteins, in particular, ApoA1 [57]. Aside from their role in cholesterol handling, the pro- and anti- inflammatory impacts of LDL and HDL on macrophages in the plaque may significantly influence macrophage contribution to overall plaque stability.
LDL

LDL is a major risk factor for atherosclerosis. Its accumulation and oxidation within the vessel wall are crucial events in plaque formation [2]. The importance of LDL in atherosclerosis development is clearly evident in Familial Hypercholesterolemia (FH) where the absence (homozygous FH) or reduction (heterozygous FH) of the LDL receptor (which removes LDL from the circulation) or its functions results in accelerated atherosclerosis development [58]. Strong evidence from many studies has demonstrated that the reduction of LDL by statin therapy is associated with reduced occurrence of vascular events [59,60]. However, despite the known detrimental role of oxLDL in atherosclerosis, it has been described to have both pro- and anti-inflammatory effects, including on macrophages [61-66]. Such discrepancies may arise from the heterogeneous nature of the modified LDL preparations used in culture. The effect of LDL uptake on macrophage phenotype depends on the degree, and form of, LDL modification [67]. For example, Miller et al. demonstrated that minimally modified LDL (mmLDL), but not LDL or oxLDL, stimulation of macrophages induced early expression of mRNA for macrophage inflammatory protein-2 (MIP-2), MCP-1, TNF-α and IL-6 [68]. MmLDL, is not sufficiently modified to be taken up by scavenger receptors but is recognized by LDL receptors and TLR4 [67,69]. Moderately oxidized LDL is taken up by Lox 1 and CD36, with more extensive oxidation required for SRA-1 engagement [67]. There are numerous biologically active compounds present in modified LDL such as modification in phospholipids, sphingolipid and free fatty acid products, oxysterols, and ApoB [67]. Their modification impacts which receptors are engaged and what cellular response occurs. For example, CD36 recognizes oxidized phospholipids; TLR-4 recognizes oxidized cholesteryl esters and SRAI/II recognizes modifications of the ApoB protein [67]. For a comprehensive review see Levitan [67]. The pro-inflammatory effects of oxLDL are mediated by NF-κB, AP-1, STAT1/, NFAT, SP-1 and HF-1[67] as well as a down regulation of KLF2 [29]. The anti-inflammatory effects of oxLDL arise from inhibition of NF-κB [6,65] and stimulation of PPARs and Nrf2 [42,67].

The cellular response of macrophages to oxLDL may also be dependent, in part, on the phenotype of the macrophage prior to oxLDL interaction. While GM-CSF derived macrophages produce higher levels of IL-6 and MCP-1 than M-CSF derived macrophages upon LPS stimulation, pre-exposure to oxLDL (prior to LPS stimulation) resulted in M-CSF derived macrophages producing higher levels of IL-6, IL-8 and MCP-1 (equivalent to that produced by LPS stimulated GM-CSF macrophages) and lower production of IL-10 compared to M-CSF alone. In contrast, no change in cytokine expression for GM-CSF derived macrophages was seen [29]. In a separate study, GM-CSF induced human macrophages exposed to oxLDL were shown to have an inhibited IL-1 and TNFα response to LPS [63]. Furthermore, M1, but not M2, macrophages exposed to oxLDL upregulated growth factor mediated NF-κB signaling pathways [70].

Most of our understanding of the effect of LDL/oxLDL on macrophage polarization comes from in vitro studies. The degree and form of LDL modification in vivo is not clear [71]. Interestingly, foam cell formation in peritoneal macrophages of an LDLR-/- mouse fed a high cholesterol/high fat diet was associated with a suppression rather than activation of inflammatory gene expression [72], suggesting that macrophage polarization to an M1 phenotype in the plaque arises from extrinsic pro-inflammatory signals. For example, foam cell necrosis is one of the factors that can stimulate an inflammatory response [5]. In addition, the necrotic core of atherosclerotic plaques is hypoxic which would be expected to promote an M1 phenotype as hypoxia switches the metabolism of macrophages to an anaerobic glycolytic pathway [73], the pathway used by M1 macrophages. Furthermore, succinate (a Krebs cycle intermediate) induces HIF1α expression which promotes expression of pro-inflammatory genes [74]. However, a separate study, using the Reversa mouse (a mouse in which hypercholesterolemia can be conditionally reversed [75]), suggests that LDL may stimulate M1 polarization, as a reduction of LDL resulted in stabilization of the plaque with decreased total macrophages (CD68 and Moma+) but increased gene expression of M2 markers such as Arg1, MR, CD163, C-lectin and FIZZ1 [76]. Whether this relates to M1 to M2 skewing, or merely an efflux of M1 macrophages is not clear.
Mox Macrophages

Of the different components of oxLDL, the effect of oxidized phospholipids on macrophage polarization has been specifically examined. Oxidized phospholipids are major contributors to oxLDL binding to scavenger receptors [77], in particular CD36 [78]. Incubation of M1 or M2 macrophages with oxidized phospholipids results in the formation of macrophages that are different from both the M1 and M2 phenotypes. This distinct phenotype has been termed the Mox macrophage [26]. It lacks CD163 which is characteristic of M2 and Mhem macrophages, however, like the Mhem macrophages, Mox express HO-1 [26]. Mox marker gene expression is largely mediated by Nrf2 (a redox-sensitive transcription factor). Whether the Mox macrophage is inflammatory/pro-atherosclerotic is not completely clear. While macrophage (MSCF or GM-CSF derived) incubation with oxidized phospholipids results in the upregulation of IL-1β, the incubation of M1 macrophages with oxidized phospholipids results in the down regulation of IL-1β, iNOS, TNFα and MCP-1 [26]. Furthermore, HO-1 is athero-protective as discussed above. However, Mox macrophages derived from M2 macrophages have reduced arginase 1 (Arg1: M2 marker) expression [26]. The ability of oxidized phospholipids to stimulate or inhibit inflammation is known to be dependent on the biological situation [79] and this appears to be the case with different macrophage phenotypes. Though Mox macrophages have been identified in the mouse, their identification in human plaques is yet to be determined.
Cholesterol crystals

Cholesterol crystals are a major feature of advanced plaques where they are readily identified by the presence of cholesterol clefts (left after tissue processing). However, their formation starts early in the plaque, even in fatty streaks [80]. Minute crystals are evident within two weeks of high cholesterol feeding in the ApoE-/- mouse which coincides with the appearance of inflammatory cells [81]. Although cholesterol crystals are primarily evident as extracellular deposits in the necrotic core, where they are proposed to arise from lipid deposition or RBC death, they can also form within macrophages themselves [81,82]. Cholesterol crystals induce NLRP3 inflammasome activation leading to the release of the inflammatory cytokines IL-1β and IL-18 in both human [83] and murine [81] macrophages.
HDL

A low level of HDL, both as reduced ApoA1 and as HDL particle cholesterol content, is associated with an increased risk of cardiovascular diseases and associated clinical events [84]. As such, HDL is considered athero-protective [85]. Indeed, infusion of HDL or ApoA1 in mouse models leads to decreased plaque size [86]. HDL/ApoA1 are known to exert anti-inflammatory actions which, while initially attributed primarily to cholesterol transport, can also be direct effects on cells [87]. Injection of ApoA1 into the ApoE-/- mouse leads to a decrease in total plaque macrophage content with a significant reduction in the expression of M1 markers (IL-1β and MCP-1) and an increase in the expression of M2 markers (Arg1 and MR) [88]. Of note, the injected ApoA1 was almost completely incorporated into HDL. Aortic segments transplanted from HDL-deficient (ApoE-/-) mice into mice with normal HDL levels (i.e. wild type mice) showed increased M2 markers (FIZZ1, Arg1, CD163, MR) and decreased inflammatory markers (MCP-1, TNFα) [89]. These findings suggest that HDL (and ApoA1) promote an M2 phenotype in vivo, but do not provide information regarding whether this is a direct effect of HDL on macrophages. To understand direct interactions, in vitro work has been conducted. Incubation of mouse bone marrow derived macrophages with HDL led to increased FIZZ1 and Arg1 expression and suppression of resting and IFNγ-induced iNOS, TNFα and IL-6, suggesting a direct effect of HDL in promoting an M2 phenotype [90]. This was proposed to be via JAK/STAT pathways, specifically JAK1 or JAK 2 interacting with STAT6 [90]. Macrophages incubated with ApoA1 had decreased LPS-stimulated production of IL-1β, IL-6 and TNFα, with this anti-inflammatory effect attributed to the interaction between ApoA1 and ABCA1, which subsequently activated the JAK2/STAT3 pathway [91]. As well as altering macrophage polarization, HDL and ApoA1 have been shown to decrease TNFα-mediated adhesion of monocytes to endothelial cells in vitro, thus showing further anti-inflammatory effects [92].

In humans, administration of reconstituted HDL leads to improved plaque composition and even regression [93,94]. However, examination of effects of HDL at the cellular level in humans becomes difficult as the plaque cannot be readily removed for analysis. As such, work examining the anti-inflammatory effects of HDL in humans predominantly consists of ex vivo and in vitro studies. Infusion of recombinant HDL led to decreases in inflammatory parameters such as reduced CD11b expression on monocytes [95]. Anti-inflammatory changes such as this suggest that high HDL promotes a shift towards an M2 macrophage phenotype and conversely, a shift away from an M2 phenotype with lower HDL levels. In contradiction to this, monocytes isolated from patients with low HDL were equally able to become M2 macrophages under IL-4 stimulation as those from patients with normal HDL levels, suggesting low HDL levels do not lead to reduced formation of M2 macrophages [96]. However, the in vivo environment is much more complex, with other factors influencing macrophage polarization coming into play, as such the possibility of low-HDL patients having reduced numbers of, or capacity to form, M2 macrophages cannot yet be ruled out. While human monocyte-derived macrophages incubated with HDL did not show increased gene expression of M2 polarisation markers (MR, CD200R, F13A1, Stabilin-1, IL1RA, CD163, IL-10, PPARγ) [96], the HDL concentrations used were low and it is possible that more physiological concentrations of HDL could lead to changes in marker expression. More in vitro work, similar to that done for mice, may determine whether, and how, HDL and its components affect macrophage polarization and function. The mechanisms by which changes in macrophage polarization occur in mice may also be active in humans.
Conclusion

The microenvironment influences the phenotype of macrophages in the atherosclerotic plaque and, as such, a range of macrophage phenotypes are present. One key factor in their environment is lipid, in particular oxLDL with its bioactive components and cholesterol crystals. A bidirectional relationship exists between macrophages and cholesterol where the phenotype of the macrophage affects its ability to handle lipid. Conversely, oxLDL or interaction with cholesterol crystals influences macrophage phenotype. However, whether the response generated promotes or suppresses inflammation depends on the degree and form of LDL modification. This complex interplay, both pro- and anti-inflammatory, is clearly swayed (albeit by other factors in the milieu as well) towards a pro-atherogenic process in cardiovascular diseases. However, mouse models in particular demonstrate that the atherogenic balance can be switched to promote plaque regression accompanied by macrophage polarization to an M2 macrophage. This suggests that despite the complexity of the plaque, key figures such as HDL and PPARs may be able to delay and reverse atherosclerosis development, with this being, in part, through modulating macrophage polarization.
Author Contribution

Heather Medbury and Helen Williams drafted the manuscript. All authors read through and made suggestions and corrections to the manuscript. All authors approved the final manuscript.
References

  1. Williams KJ, Tabas I (1995) The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 15: 551-561.

  2. Tabas I, Williams KJ, Boren J (2007) Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116: 1832-1844.

  3. Zaman AG, Helft G, Worthley SG, Badimon JJ (2000) The role of plaque rupture and thrombosis in coronary artery disease. Atherosclerosis 149: 251-266.

  4. Schrijvers DM, De Meyer GR, Kockx MM, Herman AG, Martinet W (2005) Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol 25: 1256-1261.

  5. Tabas I (2010) Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10: 36-46.

  6. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958-969.

  7. Stanley ER, Chen DM, Lin HS (1978) Induction of macrophage production and proliferation by a purified colony stimulating factor. Nature 274: 168-170.

  8. Scheuerer B, Ernst M, Dürrbaum-Landmann I, Fleischer J, Grage-Griebenow E, et al. (2000) The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 95: 1158-1166.

  9. Clinton SK, Underwood R, Hayes L, Sherman ML, Kufe DW, et al. (1992) Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. Am J Pathol 140: 301-316.

  10. Plenz G, Koenig C, Severs NJ, Robenek H (1997) Smooth muscle cells express granulocyte-macrophage colony-stimulating factor in the undiseased and atherosclerotic human coronary artery. Arterioscler Thromb Vasc Biol 17: 2489-2499.

  11. Pitsilos S, Hunt J, Mohler ER, Prabhakar AM, Poncz M, et al. (2003) Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters. Thromb Haemost 90: 1112-1120.

  12. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32: 593-604.

  13. Frostegard J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, et al. (1999) Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 145: 33-43.

  14. Mallat Z, Heymes C, Ohan J, Faggin E, Leseche G, et al. (1999) Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler Thromb Vasc Biol 19: 611-616.

  15. Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, et al. (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6: 137-143.

  16. Gleissner CA, Shaked I, Erbel C, Böckler D, Katus HA, et al. (2010) CXCL4 downregulates the atheroprotective hemoglobin receptor CD163 in human macrophages. Circ Res 106: 203-211.

  17. Khallou-Laschet J, Varthaman A, Fornasa G, Compain C, Gaston AT, et al. (2010) Macrophage plasticity in experimental atherosclerosis. PLoS One 5: e8852.

  18. Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, et al. (2011) Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARgamma and LXRalpha pathways. Circ Res 108: 985-995.

  19. Medbury HJ, James V, Ngo J, Hitos K, Wang Y, et al. (2013) Differing association of macrophage subsets with atherosclerotic plaque stability. Int Angiol 32: 74-84.

  20. Boyle JJ, Johns M, Kampfer T, Nguyen AT, Game L, et al. (2012) Activating transcription factor 1 directs Mhem atheroprotective macrophages through coordinated iron handling and foam cell protection. Circ Res 110: 20-33.

  21. Finn AV, Nakano M, Polavarapu R, Karmali V, Saeed O, et al. (2012) Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol 59: 166-177.

  22. Boyle JJ, Harrington HA, Piper E, Elderfield K, Stark J, et al. (2009) Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 174: 1097-1108.

  23. Bobryshev YV, Lord RS (1995) S-100 positive cells in human arterial intima and in atherosclerotic lesions. Cardiovasc Res 29: 689-696.

  24. Bobryshev YV, Lord RS, Rainer S, Jamal OS, Munro VF (1996) Vascular dendritic cells and atherosclerosis. Pathol Res Pract 192: 462-467.

  25. Medbury HJ, Tarran SL, Guiffre AK, Williams MM, Lam TH, et al. (2008) Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes. Int Angiol 27: 114-123.

  26. Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, et al. (2010) Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res 107: 737-746.

  27. Waldo SW, Li Y, Buono C, Zhao B, Billings EM, et al. (2008) Heterogeneity of human macrophages in culture and in atherosclerotic plaques. Am J Pathol 172: 1112-1126.

  28. Gleissner CA (2012) Macrophage Phenotype Modulation by CXCL4 in Atherosclerosis. Front Physiol 3: 1.

  29. van Tits LJ, Stienstra R, van Lent PL, Netea MG, Joosten LA, et al. (2011) Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: a crucial role for Krüppel-like factor 2. Atherosclerosis 214: 345-349.

  30. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, et al. (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41: 14-20.

  31. Martinez FO, Gordon S, Locati M, Mantovani A (2006) Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 177: 7303-7311.

  32. Beyer M, Mallmann MR, Xue J, Staratschek-Jox A, Vorholt D, et al. (2012) High-resolution transcriptome of human macrophages. PLoS One 7: e45466.

  33. Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD (2007) Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol 178: 5245-5252.

  34. Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, et al. (1993) CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem 268: 11811-11816.

  35. Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, et al. (2002) Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem 277: 49982-49988.

  36. Gleissner CA, Shaked I, Little KM, Ley K (2010) CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J Immunol 184: 4810-4818.

  37. Sachais BS, Turrentine T, Dawicki McKenna JM, Rux AH, Rader D, et al. (2007) Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE-/- mice. Thromb Haemost 98: 1108-1113.

  38. Hoeksema MA, Stoger JL, de Winther MP. (2012) Molecular pathways regulating macrophage polarization: implications for atherosclerosis. Curr Atheroscler Rep 14: 254-263.

  39. Moore KJ, Sheedy FJ, Fisher EA (2013) Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 13: 709-721.

  40. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, et al. (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40: 274-288.

  41. Wolfs IM, Donners MM, de Winther MP. (2011) Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation. Thromb Haemost 106: 763-771.

  42. Oh J, Riek AE, Weng S, Petty M, Kim D, et al. (2012) Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem 287: 11629-11641.

  43. Nakagawa T, Nozaki S, Nishida M, Yakub JM, Tomiyama Y, et al. (1998) Oxidized LDL increases and interferon-gamma decreases expression of CD36 in human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol 18: 1350-1357.

  44. Seimon T, Tabas I (2009) Mechanisms and consequences of macrophage apoptosis in atherosclerosis. J Lipid Res 50 Suppl: S382-387.

  45. Isa SA, Ruffino JS, Ahluwalia M, Thomas AW, Morris K, et al. (2011) M2 macrophages exhibit higher sensitivity to oxLDL-induced lipotoxicity than other monocyte/macrophage subtypes. Lipids Health Dis 10: 229.

  46. Korns D, Frasch SC, Fernandez-Boyanapalli R, Henson PM, Bratton DL (2011) Modulation of macrophage efferocytosis in inflammation. Front Immunol 2: 57.

  47. Stöger JL, Gijbels MJ, van der Velden S, Manca M, van der Loos CM, et al. (2012) Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis 225: 461-468.

  48. Cho KY, Miyoshi H, Kuroda S, Yasuda H, Kamiyama K, et al. (2013) The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery. J Stroke Cerebrovasc Dis 22: 910-918.

  49. Michel JB, Virmani R, Arbustini E, Pasterkamp G (2011) Intraplaque haemorrhages as the trigger of plaque vulnerability. Eur Heart J 32: 1977-198, 1985a, 1985b, 1985c.

  50. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, et al. (2003) Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 349: 2316-2325.

  51. Madsen M, Graversen JH, Moestrup SK (2001) Haptoglobin and CD163: captor and receptor gating hemoglobin to macrophage lysosomes. Redox Rep 6: 386-388.

  52. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, et al. (2001) Identification of the haemoglobin scavenger receptor. Nature 409: 198-201.

  53. Boyle JJ (2012) Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage. Curr Opin Lipidol 23: 453-461.

  54. Otterbein LE, Soares MP, Yamashita K, Bach FH (2003) Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 24: 449-455.

  55. Boyle JJ, Johns M, Lo J, Chiodini A, Ambrose N, et al. (2011) Heme induces heme oxygenase 1 via Nrf2: role in the homeostatic macrophage response to intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 31: 2685-2691.

  56. Sato T, Kameyama T, Noto T, Inoue H (2014) Impaired macrophage production of anti-atherosclerotic interleukin-10 induced by coronary intraplaque hemorrhage in patients with acute coronary syndrome and hyperglycemia. J Diabetes Complications 28: 196-202.

  57. Jessup W, Gelissen IC, Gaus K, Kritharides L (2006) Roles of ATP binding cassette transporters A1 and G, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages. Curr Opin Lipidol 17: 247-257.

  58. Motulsky AG (1989) Genetic aspects of familial hypercholesterolemia and its diagnosis. Arteriosclerosis 9: I3-7.

  59. Cholesterol Treatment Trialists (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, et al. (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376: 1670-1681.

  60. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, et al. (2012) The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380: 581-590.

  61. Thomas CE, Jackson RL, Ohlweiler DF, Ku G (1994) Multiple lipid oxidation products in low density lipoproteins induce interleukin-1 beta release from human blood mononuclear cells. J Lipid Res 35: 417-427.

  62. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, et al. (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11: 155-161.

  63. Ohlsson BG, Englund MC, Karlsson AL, Knutsen E, Erixon C, et al. (1996) Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1beta in macrophages. J Clin Invest 98: 78-89.

  64. Lipton BA, Parthasarathy S, Ord VA, Clinton SK, Libby P, et al. (1995) Components of the protein fraction of oxidized low density lipoprotein stimulate interleukin-1 alpha production by rabbit arterial macrophage-derived foam cells. J Lipid Res 36: 2232-2242.

  65. Chung SW, Kang BY, Kim SH, Pak YK, Cho D, et al. (2000) Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. J Biol Chem 275: 32681-32687.

  66. Chávez-Sánchez L, Garza-Reyes MG, Espinosa-Luna JE, Chávez-Rueda K, Legorreta-Haquet MV, et al. (2014) The role of TLR, TLR4 and CD36 in macrophage activation and foam cell formation in response to oxLDL in humans. Hum Immunol 75: 322-329.

  67. Levitan I, Volkov S, Subbaiah PV (2010) Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid Redox Signal 13: 39-75.

  68. Miller YI, Viriyakosol S, Worrall DS, Boullier A, Butler S, et al. (2005) Toll-like receptor 4-dependent and -independent cytokine secretion induced by minimally oxidized low-density lipoprotein in macrophages. Arterioscler Thromb Vasc Biol 25: 1213-1219.

  69. Choi SH, Harkewicz R, Lee JH, Boullier A, Almazan F, et al. (2009) Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake. Circ Res 104: 1355-1363.

  70. Hirose K, Iwabuchi K, Shimada K, Kiyanagi T, Iwahara C, et al. (2011) Different responses to oxidized low-density lipoproteins in human polarized macrophages. Lipids Health Dis 10: 1.

  71. Steinberg D (2009) The LDL modification hypothesis of atherogenesis: an update. J Lipid Res 50 Suppl: S376-381.

  72. Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, et al. (2012) Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 151: 138-152.

  73. Riboldi E, Porta C, Morlacchi S, Viola A, Mantovani A, et al. (2013) Hypoxia-mediated regulation of macrophage functions in pathophysiology. Int Immunol 25: 67-75.

  74. Galván-Peña S, O'Neill LA (2014) Metabolic reprograming in macrophage polarization. Front Immunol 5: 420.

  75. Lieu HD, Withycombe SK, Walker Q, Rong JX, Walzem RL, et al. (2003) Eliminating atherogenesis in mice by switching off hepatic lipoprotein secretion. Circulation 107: 1315-1321.

  76. Feig JE, Parathath S, Rong JX, Mick SL, Vengrenyuk Y, et al. (2011) Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques. Circulation 123: 989-998.

  77. Hörkkö S, Bird DA, Miller E, Itabe H, Leitinger N, et al. (1999) Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest 103: 117-128.

  78. Podrez EA, Poliakov E, Shen Z, Zhang R, Deng Y, et al. (2002) Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36. J Biol Chem 277: 38503-38516.

  79. Bochkov VN (2007) Inflammatory profile of oxidized phospholipids. Thromb Haemost 97: 348-354.

  80. Guyton JR, Klemp KF (1993) Transitional features in human atherosclerosis. Intimal thickening, cholesterol clefts, and cell loss in human aortic fatty streaks. Am J Pathol 143: 1444-1457.

  81. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, et al. (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464: 1357-1361.

  82. Tangirala RK, Jerome WG, Jones NL, Small DM, Johnson WJ, et al. (1994) Formation of cholesterol monohydrate crystals in macrophage-derived foam cells. J Lipid Res 35: 93-104.

  83. Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, et al. (2010) Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 5: e11765.

  84. Ishikawa T, Fidge N, Thelle DS, Forde OH, Miller NE (1978) The Tromso Heart Study: serum apolipoprotein AI concentration in relation to future coronary heart disease. Eur J Clin Invest 8: 179-182.

  85. Säemann MD, Poglitsch M, Kopecky C, Haidinger M, Hörl WH, et al. (2010) The versatility of HDL: a crucial anti-inflammatory regulator. Eur J Clin Invest 40: 1131-1143.

  86. Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, et al. (2002) Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 105: 290-292.

  87. Yvan-Charvet L, Wang N, Tall AR (2010) Role of HDL, ABCA, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol 30: 139-143.

  88. Hewing B, Parathath S, Barrett T, Chung WK, Astudillo YM, et al. (2014) Effects of native and myeloperoxidase-modified apolipoprotein a-I on reverse cholesterol transport and atherosclerosis in mice. Arterioscler Thromb Vasc Biol 34: 779-789.

  89. Feig JE, Rong JX, Shamir R, Sanson M, Vengrenyuk Y, et al. (2011) HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc Natl Acad Sci U S A 108: 7166-7171.

  90. Sanson M, Distel E, Fisher EA (2013) HDL induces the expression of the M2 macrophage markers arginase 1 and Fizz-1 in a STAT6-dependent process. PLoS One 8: e74676.

  91. Tang C, Liu Y, Kessler PS, Vaughan AM, Oram JF (2009) The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. J Biol Chem 284: 32336-32343.

  92. Murphy AJ, Hoang A, Aprico A, Sviridov D, Chin-Dusting J (2013) Anti-inflammatory functions of apolipoprotein A-I and high-density lipoprotein are preserved in trimeric apolipoprotein A-I. J Pharmacol Exp Ther 344: 41-49.

  93. Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, et al. (2007) Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 297: 1675-1682.

  94. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, et al. (2003) Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290: 2292-2300.

  95. Patel S, Drew BG, Nakhla S, Duffy SJ, Murphy AJ, et al. (2009) 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 53: 962-971.

  96. Colin S, Fanchon M, Belloy L, Bochem AE, Copin C, et al. (2014) HDL does not influence the polarization of human monocytes toward an alternative phenotype. Int J Cardiol 172: 179-184.

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