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Macrophage Foam Cells
Chapter · September 2010
DOI: 10.1002/9780470015902.a0020730
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Macrophage Foam Cells
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Article Contents
Annabel F Valledor, University of Barcelona, Barcelona, Spain
Jorge Lloberas, University of Barcelona, Barcelona, Spain
Antonio Celada, University of Barcelona, Barcelona, Spain
• Introduction
• Macrophages
• Macrophages and Inflammation
• Conversion of Macrophages into Foam Cells
Based in part on the previous version of this eLS article ‘Macrophage
Foam Cells’ (2010) by Annabel F Valledor, Jorge Lloberas and Antonio
Celada.
• Macrophages in the Development
of Atherosclerotic Lesions
• Transcriptional Control to Prevent Foam Cell
Formation and the Development
of Atherosclerosis
• Foam Cells in Other Forms of Chronic
Inflammation
Online posting date: 16th February 2015
Foam cells are lipid-loaded macrophages that are
generated from the massive uptake of modified
low-density lipoproteins and the intracytoplasmatic accumulation of cholesteryl esters. Foam
cells are present in all stages of atherosclerosis
and participate in inflammatory responses and
tissue remodelling within the arterial intima.
Foam cells can also be generated as a consequence
of infection by persistent pathogens, such as
Mycobacterium, Chlamydia and Toxoplasma. These
pathogens meet nutritional advantages by residing within cells that accumulate lipids. When the
immune system is unable to eliminate substances
perceived as foreign, it produces a granuloma,
composed mostly of macrophages, attempting to
wall off the non-self material. This article reviews
the processes that lead to the regulation of foam
cell formation in atherosclerosis and infection.
Introduction
In the mid-nineteenth century, Rudolf Virchow postulated that
cellular pathology is critical in atherosclerosis (reviewed by
Mayerl et al., 2006). However, only in recent years has the inflammatory process leading to atherosclerosis been characterised.
Today, we know that foam cells are lipid-laden macrophages
present in all stages of atherosclerosis. Foam cells play a major
role in the formation of the fatty-streak, the earliest pathological
sign of atherosclerosis, and in the progression and pathogenicity
eLS subject area: Cell Biology
How to cite:
Valledor, Annabel F; Lloberas, Jorge; and Celada, Antonio
(February 2015) Macrophage Foam Cells. In: eLS. John Wiley &
Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0020730.pub2
of established atherosclerotic plaques. Thus, foam cells are
considered therapeutic targets for the treatment of atherosclerosis
(Saha et al., 2009). These cells have also been detected in other
forms of chronic inflammation, including septic arthritic lesions
and in tissues infected by persistent pathogens such as Mycobacterium, Chlamydia and Toxoplasma (Portugal et al., 2008).
Macrophages
Macrophages play a critical role in tissue homeostasis and
immunity. The use of multicolour fluorescence-activated cell
sorting together with adoptive transfer of precursors has helped
characterise in vivo differentiation of macrophage populations.
Like many other cells in the immune system, blood monocytes and many macrophage subsets originate from pluripotent
haematopoietic stem cell within the bone marrow. Successive
commitment steps generate macrophage/dendritic cell progenitors that differentiate to monocytes, which then leave the bone
marrow and travel through the blood to other tissues in the
body (Geissmann et al., 2010). In an adult, the bone marrow
releases approximately 5 × 109 monocytes daily and most of
these cells are short-lived. Under normal conditions, a few of
these monocytes (patrolling monocytes) enter tissues and differentiate into macrophages. Recently, it has been shown that
in many tissues (i.e. brain, skin and liver) resident macrophage
populations derive from yolk sac precursors that colonise their
target tissues during embryogenesis and form stable networks
within these tissues by differentiation in situ. Such macrophage
populations self-renew in the steady state and do not depend
on continuous replacement by the bone marrow (reviewed by
Ginhoux and Jung, 2014). Depending on the specific location, resident macrophages are given different names that may
be associated with specialised functional activities (e.g. osteoclasts in the bone, alveolar macrophages in the lung, histiocytes
in the connective tissue, mesangial cells in the kidney, sinusoidal lining cells in the spleen, microglia in the brain, Kupffer
cells in the liver and Langerhans cells in the skin). See also:
Macrophages
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1
Macrophage Foam Cells
Macrophages are approximately 21 μm in diameter and
can be identified by the specific expression of a number
of proteins, including CD14, CD11b, F4/80 (mice)/EMR1
(humans), lysozyme M, MAC-3 and CD68 (Yona and Jung,
2010). Macrophages are versatile cells that have multiple activities inside and outside the immune system. The initial function
that was associated with these cells is phagocytosis, which is
the capacity to engulf and digest pathogens, cellular debris and
apoptotic bodies (Paidassi et al., 2009). Phagocytosis is part of
the non-specific immune defence response (or innate immunity).
After the pathogen is recognised as foreign material by specific
pathogen-associated molecular pattern receptors, the phagocytic
cell makes temporary extensions of the cell membrane to surround the pathogenic particle and internalise it within vacuoles
(phagosomes). Phagosomes then fuse with lysosomes to make
phagolysosomes, in which a number of enzymes and other
toxic products destroy the microorganisms (Flannagan et al.,
2009). ‘Foreign’ proteins derived from these microorganisms
are hydrolysed, thus generating peptides (small fragments of
proteins). Part of these peptides is released to the extracellular
medium as waste. Released peptides can then be recognised
by B lymphocytes through their surface immunoglobulins, a
process that leads to B lymphocyte activation. Some of the
protein fragments are further processed into short peptides inside
macrophages (10–14 amino acids in length) and are inserted
into the antigen-presenting groove of major histocompatibility
complex (MHC) molecules for subsequent export to the cell
membrane. These peptide–MHC complexes are then presented
to T lymphocytes through a process known as antigen presentation. If the interacting T lymphocyte displays the appropriate
T cell receptor (TCR) for the peptide–MHC combination, the T
lymphocyte will be activated and stimulated to release cytokines
that modulate the immune response (Hume, 2008). These are
the early events of the specific immune defence (or adaptive
immunity). With the coordinated action of T and B lymphocytes,
the process of antigen presentation may result in the production
of specific antibodies that attach to antigens on the surface of
pathogens (opsonisation). Opsonised particles are more efficiently recognised by macrophages, thus resulting in enhanced
phagocytosis and clearance of the foreign particles. See also:
Phagocytosis; Phagocytosis: Enhancement
During the immune response, macrophages are also involved
in the production of pro-inflammatory mediators, including
enzymes, nitrogen and oxygen reactive species, complement
proteins and cytokines that control the functional activity of
other cells. For example, the cytokines tumour necrosis factor
α (TNFα) and interleukin-1 beta (IL-1β) released by activated
macrophages act in the hypothalamus to induce fever. Overproduction of these cytokines during septic shock can lead to
multi-organ failure and the death of the organism (Lloberas and
Celada, 2009). See also: Inflammatory Mediators
Finally, macrophages are also implicated in the maintenance
of homeostasis. For example, spleen macrophages recognise cell
surface markers that are expressed on aged red blood cells. After
phagocytosis of these cells, some of their contents are recycled,
including iron molecules, and later released by macrophages to
the plasma depending on the needs of the organism to produce
more red blood cells in the bone marrow (Beaumont and Delaby,
2
2009). Macrophages also control lipid metabolism, as described
later. See also: Spleen
Macrophages and Inflammation
Nowadays, we know that inflammation represents a major factor
in the development of a number of chronic diseases, such as cancer, metabolic syndrome, autoimmunity and neurodegenerative
disorders. For this reason, many novel strategies for therapeutic
intervention of several chronic diseases aim at interfering with
the inflammatory process, and in particular, with the activities of
macrophages.
The expression of selected surface molecules allows us to
distinguish among different monocyte subsets in circulation. In
humans, expression of CD16 (also known as Fc-gamma receptor III, FcγRIII) distinguishes two monocyte subsets. Most of
the circulating monocytes (80–90%) are CD14+ /CD16− cells
that express high levels of the chemokine receptor CCR2 and
low levels of CX3CR1. These monocytes are poor producers
of inflammatory cytokines and they preferentially release the
anti-inflammatory cytokine IL-10. Conversely, CD16+ monocytes express high levels of CX3CR1 and low levels of CCR2
and account for inflammatory cytokine production. In the mouse,
monocyte subsets can be distinguished on the basis of the expression of the Ly6C antigen and of the chemokine receptors CCR2
and CX3CR1. Ly6C− monocytes patrol blood vessels under
steady-state conditions, whereas monocytes that express Ly6C
and high levels of CCR2 are recruited at sites of inflammation
and in lymph nodes and secrete large amounts of inflammatory
cytokines (Geissmann et al., 2003; Mantovani et al., 2009). When
inflammation takes place, the bone marrow generates Ly6C+
monocytes that strongly interact with endothelial cells lining the
blood vessels at the inflammatory loci and then enter the damaged tissue through a process known as extravasation, where they
undergo the morphological and functional changes that lead to
differentiation into activated tissue macrophages.
During the initial phases of the inflammatory process and in
response to several cytokines (e.g. interferon γ, IFNγ) or bacterial
products such as lipopolysaccharide (LPS), macrophages become
‘classically activated’ and exert strong pro-inflammatory activities through the release of a number of toxic compounds such as
nitric oxide (NO) and reactive oxygen species (ROS). During the
progression of inflammation, macrophages phagocytose apoptotic bodies derived from neutrophils, macrophages or other cells
present at the inflammatory site. Extensive phagocytosis makes
macrophages switch phenotype to become anti-inflammatory
cells with active roles in tissue repair (Arnold et al., 2007). See
also: Inflammatory Mediators
Conversion of Macrophages into
Foam Cells
Macrophages play a major role in lipoprotein homeostasis.
Under normal conditions, macrophages take up low-density
lipoproteins (LDLs) through LDL receptors (LDLRs). After
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Macrophage Foam Cells
internalisation, LDL particles are degraded in the lysosomal
compartment, where enzymes hydrolyse cholesteryl esters to
free cholesterol and fatty acids. Free cholesterol is toxic and
needs to be re-esterified into cholesteryl esters for storage as lipid
droplets in the cytoplasm. The dynamic balance between the
amount of free cholesterol and cholesteryl esters within the cell is
regulated by two enzymes located in the endoplasmic reticulum:
acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) and
neutral cholesterol ester hydrolases (nCEH) (reviewed by Li
and Palinski, 2006). In normal conditions, free cholesterol and
phospholipids are mobilised to the plasma membrane by adenosine triphosphate-binding cassette (ABC) transporters, including
ABCA1 and G1, and subsequently transferred to exogenous
apolipoprotein acceptors that make up high-density lipoproteins
(HDLs). This process is known as cholesterol efflux and it is
the first step in reverse cholesterol transport from peripheral
tissues to the liver. Human genetic deficiency in ABCA1 leads
to Tangier disease, a condition characterised by severe HDL
deficiency, the accumulation of foam cells in many tissues and
an increased susceptibility to develop atherosclerosis (reviewed
by Takahashi et al., 2005).
Each of the lipid constituents of LDL, including cholesteryl
esters, phospholipids, sterols and triglycerides, can undergo oxidation. Under conditions that lead to the accumulation of oxidised
LDL (oxLDL) or other forms of modified LDL, macrophages
become highly efficient at taking up these particles through the
action of scavenger receptors (SR)-A, −BI and CD36, which
have evolved as molecular pattern recognition receptors to mediate phagocytosis of pathogens and apoptotic cells (reviewed
by Hazen, 2008). The accumulation of LDL derivatives inside
macrophages inhibits the surface expression of classical LDLRs
but not of scavenger receptors (Brown and Goldstein, 1986).
Thus, macrophages conserve the capacity to accumulate very
large amounts of oxLDL-derived lipids and become lipid-loaded
foam cells. See also: Macrophages in Lipid and Immune
Homeostasis
Macrophages in the Development
of Atherosclerotic Lesions
Atherosclerotic lesions arise in the arterial wall, typically at
vessel bifurcations that are exposed to non-laminar blood flow.
The intima, the arterial layer adjacent to the lumen, consists
of a monolayer of endothelial cells and an internal elastic tissue, which, in humans, is rich in proteoglycans, particularly
near branch sites. Lipid accumulation is generally absent from
healthy intima, as are macrophages, except for occasional
patrolling monocytes. Underneath the intima, a thick arterial
media, consisting mainly of smooth muscle cells interwoven
with elastin and collagen fibres, conveys mechanical stability
to the arterial wall (reviewed by Li and Palinski, 2006). The
accumulation of lipids in the arterial intima is dependent on
the interaction of LDL particles with proteoglycans within the
extracellular matrix. LDL particles may then undergo modification (e.g. oxidation) by endothelial and other arterial cells
and initiate an inflammatory process that promotes monocyte
recruitment into the vessel wall (Figure 1). Under the effect of
oxLDL, endothelial cells express adhesion molecules, including
E- and P-selectins, which interact with integrins expressed on
the surface of circulating monocytes, thus facilitating monocyte
tethering and rolling on the endothelial layer. This process
is followed by firm adhesion of monocytes on endothelial
cells mediated by endothelial expression of vascular adhesion
molecule-1 (VCAM-1) and intercellular adhesion molecule-1
(ICAM-1). Finally, transmigration through the endothelium
involves the interaction of junctional adhesion molecules (JAM)
and connexins (reviewed by Galkina and Ley, 2007).
Endothelial transmigration of monocytes is also promoted
by chemokines, such as monocyte chemoattractant protein 1
(MCP-1) and Ccl5 (also known as Rantes) (Figure 1). The
chemokine C-C receptors CCR2 and CCR5 are expressed in
monocytes and play an important role in atherosclerosis by binding to MCP-1 and Ccl5, respectively. Genetic manipulation of
these chemokine/receptor systems have been shown to affect
plaque size and progression (reviewed by Gautier et al., 2009).
Macrophage migration inhibitory factor (MIF) is a cytokine that
plays a regulatory role in monocyte adhesion and migration and
in macrophage proliferation. Increased expression of MIF has
been demonstrated in human atherosclerotic lesions, whereas the
absence of the gene encoding MIF reduces atherosclerosis in
mice (reviewed by Noels et al., 2009). See also: Atherosclerosis:
Pathogenesis, Clinical Features and Treatment
Once monocytes have taken residence in the arterial
wall intima, they undergo phenotypic transformation into
macrophages, internalise large amounts of modified LDLs via
scavenger receptors and become foam cells, as described earlier
(Figure 1). This is the initial step in formation of the fatty streak
in the arterial wall. Thus, a common strategy in reducing the risk
of atherosclerosis is currently based on lowering LDL levels in
the organism through the use of statins, inhibitors of HMG-CoA
reductase, the rate-limiting enzyme involved in the cholesterol
biosynthetic pathway. By reducing the cellular capacity to
synthesise cholesterol, LDLRs are upregulated, particularly in
hepatocytes, and they remove the circulating pro-atherogenic
LDL particles more rapidly (Brown and Goldstein, 1986).
During progression of the atherosclerotic plaque, invading
macrophages and newly formed foam cells secrete ROS and the
enzyme 12/15-lipoxygenase (LO) that contributes to enhancing the oxidation of LDL particles. Foam cells also release
pro-inflammatory cytokines (including TNF-α, IL-1β and IL-6),
chemokines, growth factors, such as platelet-derived growth
factors (PDGFs), endothelial-derived growth factor (VEGF)
and insulin-like growth factors (IGFs), and enzymes, such as
cysteine-, serine- and metallopeptidases, which degrade extracellular matrix components (reviewed by Saha et al., 2009).
The combined action of all these molecules enhances the
inflammatory process, allowing T lymphocytes, natural killer
cells, dendritic cells and mast cells to infiltrate the vascular
subendothelium. Furthermore, the proliferation and migration of
smooth muscle cells into the intima facilitates the establishment
of the atherosclerotic plaque.
At later stages of atherosclerosis, foam cells express high levels of cycloxygenases (COX)-1 and -2 (reviewed by Cipollone
et al., 2008). These are enzymes that generate pro-inflammatory
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
3
Macrophage Foam Cells
(b)
(a)
Vascular
lumen
Adhesion
Migration
MCP-1
CCR-2
ox LDL
Monocyte
Endothelial
cells
LDL
HDL
Extracellular
matrix
Differentiation
M-CSF
Intima
VCAM-1
P-selectin
E-selectin
ICAM-1
CS-1
mmLDL
Proinflamatory
process
15 LO
iNOS
Homeostatic
responses
apo E
ABC-1
ACAT
ox LDL
TNF-α
IL-1β
IL-6
Macrophage
Foam cell
ox LDL uptake
CD36
SR-A
Media
Internal elastic lamina
LDL oxidation
Smooth muscle
cells
(c)
Figure 1 Mechanisms involved in foam cell formation and development of the atherosclerotic lesion. (a) Microphotograph of the normal intima after oil-red
O staining. Very few oil-red O-positive lipid infiltrations are detected in the normal intima. (b) Microphotograph of the earliest stage of an atherosclerotic
lesion, the fatty streak, after staining with oil-red O. The fatty streak is characterised by subendothelial accumulation of macrophages/foam cells, which contain
massive amounts of lipids, as indicated by oil-red O staining. (c) Atherogenesis is a chronic inflammatory process. Under conditions of hypercholesterolaemia,
LDL accumulates in the arterial intima and is progressively oxidised by endothelial and other arterial cells. Endothelial cells also become activated, thus
increasing the expression of adhesion molecules, including selectins, VCAM-1 and ICAM-1, on their surfaces. OxLDL and MCP-1 act as chemoattractants for
circulating monocytes that then attach to endothelial cells via adhesion molecules. CCR2, the receptor for MCP-1, is upregulated in circulating monocytes
and further increases their rate of recruitment. Monocytes transmigrate to the subendothelial space, where they transform into macrophages and begin
producing enzymes that oxidatively modify LDL, such as 12/15-LO and enzymes that produce ROS. Oxidised LDL is rapidly taken up by scavenger receptors,
such as CD36 and SR-A. The rapid accumulation of cholesteryl esters results in foam cell formation. Infiltrated macrophages and foam cells also participate
in the inflammatory process by secretion of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6. Homeostatic responses to prevent accumulation of
foam cells include upregulation of the expression of molecules that participate in cholesterol efflux to HDL, such as apoE and ABCA1. Original magnification
of microphotographs is 40×. (a) and (b) were donated by Andrew C. Li (University of California, San Diego). Reproduced with permission from Glass and
Witztum (2001) © Cell Press.
prostaglandins and thromboxane A2 (TXA2), which induce
vasoconstriction and platelet aggregation. Inflammatory mediators also activate resident cells in the lesion and the secretion
of proteolytic enzymes by macrophages contributes to plaque
4
erosion and rupture by forming a surface on which activated
platelets may initiate thrombosis and amplify inflammation,
thereby leading to stroke and myocardial infarction. See also:
Cholesterol and Vascular Disease
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Macrophage Foam Cells
Transcriptional Control to Prevent
Foam Cell Formation and the
Development of Atherosclerosis
Liver X receptors (LXRs) and peroxisome proliferator-activated
receptors (PPARs) are ligand-dependent transcription factors that
belong to the nuclear receptor family. LXRs and PPARs positively regulate gene expression by binding as heterodimers with
other members of the nuclear receptor family, the retinoid X
receptors (RXRs), to specific response elements on the promoter
or enhancer regions of their target genes. Several studies suggest that LXRs and PPARs play critical roles in feed-forward
mechanisms that regulate cholesterol and fatty acid homeostasis in macrophages in response to rapid changes in cellular lipids
(reviewed by Ricote et al., 2004).
Two isoforms of LXR have been identified, LXRα and β,
both of which are activated by oxidised derivatives of cholesterol (oxysterols) (Repa and Mangelsdorf, 2000). Treatment
of cells with oxLDL leads to LXR activation, which suggests
that LXR-activating oxysterols are present in oxLDL. LXR
agonists induce in vitro cholesterol efflux from macrophages to
extracellular apoAI acceptors and inhibit the development
of atherosclerosis in mice. Moreover, the transplantation
of LXR-deficient bone marrow progenitor cells into either
apolipoprotein E (apoE)-deficient or LDLR-deficient mice leads
to an increase in atherosclerotic lesions, thereby suggesting that
activation of the LXR pathway exerts protective roles that impede
the accumulation of excess cholesterol within cells and also prevent foam cell formation and the development of atherosclerosis
(Tangirala et al., 2002). In fact, LXR–RXR heterodimers directly
upregulate the expression of a number of genes involved in lipid
and lipoprotein homeostasis, such as the cholesterol transporters
ABCA1 and G1, phospholipid transfer protein (PLTP) and apoE
(Figure 2) (reviewed by A-González and Castrillo, 2011). All
these molecules participate in promoting cholesterol efflux, thus
preventing and/or reducing cholesteryl ester accumulation in
arterial wall macrophages. Moreover, the recognition of apoE
as part of chylomicron remnants, very low-density lipoproteins (VLDLs) and intermediate density lipoproteins (IDLs) by
LDLRs facilitates hepatic uptake of lipoprotein remnants.
LXR activation also leads to the coordinated upregulation
of other apolipoproteins (apoC-I, apoC-IV and apoC-II) and
lipoprotein lipase (LPL), which affect lipoprotein metabolism
(Mak et al., 2002). For example, ApoC-II is the obligate cofactor
for LPL and is required for LPL-dependent hydrolysis of triglycerides present in chylomicrons, VLDLs and HDLs. Deficiency
of apoC-II results in hypertriglyceridaemia (Fojo and Brewer,
1992).
More recent studies have also demonstrated that LXR activation leads to increased expression of Mylip/Idol, an E3-ubiquitin
ligase that promotes degradation of several members of the LDLR
family. Therefore, the LXR pathway not only enhances mechanisms involved in cholesterol efflux but also participates in limiting the uptake of circulating LDL by macrophages and other cells
(Zelcer et al., 2009; Hong et al., 2010).
Apart from their role in reverse cholesterol transport, LXR
agonists induce the expression of the transcription factor sterol
response element binding protein (SREBP)-1c, which in turn
triggers the expression of enzymes involved in fatty acid synthesis and desaturation and triglyceride formation (Repa et al.,
2000). In macrophages, positive regulation of fatty acid biosynthesis and their use in cholesterol sterification may reflect an
adaptive mechanism provided by LXRs to buffer the toxic effects
of free cholesterol (Tabas, 2002). Moreover, desaturation of fatty
acids may provide the cell with ligands for other nuclear receptors, including PPARs (see later discussion). The finding that
lipogenesis is strongly activated by available synthetic LXR agonists limits their potential use as anti-atherogenic drugs. However,
it may be possible to develop novel ligands that differentially
regulate programs of gene expression involved in cholesterol
efflux and fatty acid biosynthesis. In the absence of activating
ligands, LXR/RXR heterodimers actively repress target genes
by binding nuclear receptor co-repressors such as NCoR and
SMRT. In LXR-deficient macrophages, NCoR is not recruited to
LXR target genes, which leads to derepression of the ABCA1
gene and enhanced cholesterol efflux, but does not result in
increased expression of SREBP1c or increased fatty acid biosynthesis (Wagner et al., 2003). Therefore, the generation of selective
LXR modulators that disrupt the binding of LXR to co-repressors
without leading to co-activator recruitment may provide a strategy to selectively increase ABCA1 expression in macrophages
and thus be used for anti-atherogenic purposes without having
side effects on lipogenesis.
Within the PPAR subfamily, three isoforms have been identified, namely PPARα, 𝛿 and γ. PPARs bind a broad range of fatty
acids and their metabolites. While there is some preference for
specific fatty acids by each PPAR, when present at sufficiently
high concentrations many fatty acids are capable of activating
all three PPAR isoforms. PPARs can be also activated by certain
eicosanoids, which are produced by metabolism of arachidonic
acids and other long-chain polyunsaturated fatty acids (reviewed
by Menendez-Gutierrez et al., 2012). PPARα is also the molecular target of fibrates, such as gemfibrizol, which are used clinically to treat hypertriglyceridaemia. Indeed, PPARα regulates
the production of enzymes involved in fatty acid β-oxidation
and lipoprotein metabolism. Clinical trials examining the effects
of fibrates in primary and secondary cardiovascular prevention
studies demonstrated a significant reduction in coronary heart disease, with highest efficacy in overweight individuals with insulin
resistance and chronic inflammation (reviewed by Bouhlel et al.,
2008).
PPARγ is activated by thiazolidinediones (TZDs), such as
rosiglitazone, which act as insulin sensitisers and have been used
in the treatment of type 2 diabetes mellitus. Oxidised lipids
present in oxLDL, such as 15-hydroxyeicosatetraenoic acid and
13-hydroxyoctadecadienoic acid, also have the capacity to activate PPARγ (reviewed by Ricote et al., 2004). The scavenger
receptor CD36, involved in oxLDL uptake, is a PPARγ target
gene (Figure 2). However, despite increased CD36 expression,
TZDs do not induce significant cellular cholesterol accumulation (Moore et al., 2008). Indeed, PPARγ agonists reduce carotid
artery wall thickening in diabetic patients and direct evidence that
PPARγ exerts anti-atherogenic action has been shown in murine
models of atherosclerosis (reviewed by Li and Palinski, 2006).
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5
Macrophage Foam Cells
oxLDL
apoptotic cells
Triglyceride-rich
lipoproteins
LPL
SRs
CD36
FFAs
PGs, LTs
Cholesterol
Oxysterols
PLA2
FAS
PPARE TATA
PPAR/RXR
Cxcl10
MIG
IL12p40
iNOS
LXRE TATA
RXR/LXR
CD36
iNOS
COX2
LXRα
Cpt1
IL-1β
Ech1
IL-6
Pex11a
MMP-9
LPL
MCP-1,-3
MIP-1β
Cxcl10
ABCA1
ABCG1
apoE
LPL
PLTP
SREBP1c
Mylip/Idol
FFAs
Cholesterol efflux
Cpt1 Ech1 Pex11a
Mitochondria
β-oxidation
ACAT
Cholesterol
Cholesterol
esters
ABCA1
apoAI
apoE
Figure 2 Macrophage responses to PPAR and LXR activation. Macrophages have availability to free fatty acids (FFAs) via the action of fatty acid synthase
(FAS) or phospholipase A2 (PLA2) or via LPL-mediated lipolysis of triglyceride-rich lipoproteins. Conversion of FFAs to eicosanoids, such as prostaglandins (PGs)
and leucotriens (LTs), provides ligands for PPARs. On the other hand, the uptake of oxLDL by SRs, including CD36, provides oxysterols that can activate
LXRs. Activated PPARs and LXRs upregulate the expression of target genes through heterodimerisation with RXR and binding to the response elements
PPARE and LXRE, respectively. Both PPARs and LXRs induce the expression of genes involved in macrophage lipid homeostasis (in red). For example, PPARs
upregulate the expression of genes involved in mitochondrial β-oxidation, including Cpt1, Ech1 and PexIIa, and LXRs induce the expression of genes that
participate in cholesterol efflux, such as ABCA1 and apoE. PPARs and LXRs also participate in modulation of innate and acquired immunity by transrepressing
the expression of selective subsets of pro-inflammatory genes each (in blue). MIG, macrophage induced gene; iNOS, inducible nitric oxide synthase; MIP,
macrophage inflammatory protein. Adapted from Ricote et al. (2004). © American Heart Association.
In agreement with this, reconstitution of the haematopoietic system of LDLR-deficient mice with PPARγ-null bone marrow progenitor cells results in increased atherosclerosis (Chawla et al.,
2001). There are several points of cross-talk between PPARs and
LXRs in the regulation of cholesterol homeostasis. PPARα and γ
induce the expression of ABCA1 and stimulate cholesterol efflux
in human primary and THP-1 macrophages through a transcriptional cascade mediated by LXRα (Chawla et al., 2001; Chinetti
et al., 2001). Consistent with these findings, basal cholesterol
efflux from cholesterol-loaded macrophages to HDL is significantly reduced after disruption of the PPARγ gene (Akiyama
6
et al., 2002). Microarray analysis suggests that most PPARγ target genes, such as CD36, apoE, adipose differentiation-related
protein (ADRP), ABCG1, the peroxisomal enzymes Ech1 and
Pex11a, α mannosidase II and carnitine palmitoyl transferase
(Cpt1), participate in lipid transport and metabolism. Interestingly, some of the target genes for PPARγ are also induced by
PPAR𝛿 ligands, suggesting that these two isoforms have overlapping transactivator functions in macrophages (reviewed by Ricote
et al., 2004).
In addition to the regulation of lipid metabolism, LXRs and
PPARγ exert both overlapping and specific repressive actions
on transcriptional programs induced during the macrophage
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Macrophage Foam Cells
response to inflammatory stimuli, affecting a number of
genes that code for mediators of innate and acquired immune
responses (Ghisletti et al., 2007). Most probably, these effects
result from a combination of mechanisms, including nuclear
receptor-mediated transrepression. LXRs and PPARγ also exert
anti-inflammatory effects in several in vivo murine models of
inflammation, including atherosclerosis (reviewed by Ricote
et al., 2004). In humans, rosiglitazone reduces the circulating concentrations of inflammatory markers of cardiovascular
disease, such as C-reactive protein, matrix metallopeptidase
(MMP)-9 and TNF-α, in type 2 diabetic patients (Haffner et al.,
2002). In the past few years, significant progress has been made
in our understanding of the molecular mechanisms governing
the transrepression of inflammatory responses by LXRs and
PPARγ. Agonists for LXRs or PPARγ inhibit NF𝜅B-mediated
responses through alternative sumoylation-dependent mechanisms. Ligand-dependent conjugation of SUMO2/3 to LXRs or
SUMO1 to PPARγ targets them to promoters of genes induced
upon toll-like receptor (TLR) engagement, where they prevent the signal-dependent removal of co-repressor complexes
(Ghisletti et al., 2007). More recently, LXR has been shown to
downregulate a large percentage of the macrophage transcriptional response to IFNγ in a sumoylation-dependent manner,
which correlated with reduced recruitment of signal transducer
and activator of transcription (Stat)1 to several gene promoters
(Pascual-García et al., 2013). These observations led to the notion
that LXR and PPAR agonists exert their anti-atherogenic effect
not only by promoting cholesterol efflux but also by limiting the
production of inflammatory mediators in the arterial wall.
Taking all these considerations together, the activation of
LXRs and PPARs by constituents of oxLDL or other endogenous ligands should lead to cholesterol efflux and inhibition of
macrophage inflammatory responses, thereby preventing foam
cell accumulation. However, this protective system cannot compensate the effects of cholesterol-rich western diets indefinitely.
The mechanisms that shut off the protective actions of nuclear
receptors are not well understood. Interestingly, IFNγ and LPS
repress the expression of PPARγ (Welch et al., 2003) and both
IFNγ and TLR signalling inhibit macrophage responses to LXR
agonists, such as induction of ABCA1 and cholesterol efflux
(Castrillo et al., 2003; Pascual-García et al., 2013). These observations suggest that inflammatory events within the arterial
wall reciprocally contribute to the inhibition of nuclear receptor action. On the other hand, an LXR transcriptional target,
the scavenger glycoprotein AIM (apoptosis inhibitory protein
secreted by macrophages)/Sp-α protects macrophages from the
apoptotic effects of oxidised lipids (Arai et al., 2005) and recent
work has provided evidence that overexpression of human AIM
increases foam cell formation by promoting CD36-mediated
uptake of oxLDL (Amézaga et al., 2014). On the basis of these
observations, it is possible that positive regulation of AIM and
CD36 expression by endogenous LXR and PPAR ligands, respectively, in coordination with a local inflammatory environment that
inhibits LXR-dependent cholesterol efflux may contribute to the
loss of the protective activities mediated by these nuclear receptors during development of atherosclerosis. See also: Nuclear
Receptors and Disease; Nuclear Receptor Genes
Foam Cells in Other Forms
of Chronic Inflammation
When the immune system is unable to eliminate substances
perceived as foreign, both infectious and non-infectious, it produces a ball-like structure of immune cells attempting to wall
off the non-self material. This special type of inflammatory reaction is called granuloma and occurs in a wide variety of diseases (Figure 3). Granuloma is an organised collection composed
mostly of macrophages that are typically so tightly clustered
that the borders of individual cells are difficult to appreciate and
often, but not invariably, fuse to form multi-nucleated giant cells.
Granulomas may also contain matrix components, including collagen, and additional cells such as lymphocytes, neutrophils,
eosinophils, multi-nucleated giant cells and fibroblasts. T cells
of the IFNγ-secreting TH 1 subset surround the granuloma. See
also: Immune Mechanisms against Intracellular Pathogens;
Inflammation: Chronic
During infection, lipid bodies can be generated within infected
cells. Formation of lipid bodies in this context is dependent on
the activation of TLRs and the presence of pro-inflammatory signals such as TNFα and MCP-1. In infections by Mycobacterium
tuberculosis, lipids are overproduced by bacilli that reside within
macrophages. These lipids consolidate as multi-vesicular bodies and are subsequently exocytosed to the extracellular milieu
(Figure 3). The most bioactive components of these released
lipids are trehalose dimycolates (TDM). It has been recently
demonstrated that foam cell formation can be specifically induced
by oxygenated forms of mycolic acid, such as oxygenated ketomycolic and hydroxyl-mycolic acids. These lipids are synthesised
by pathogenic mycobacterial species such as Mycobacterium
avium and M. tuberculosis but not by saprophytic species such
as M. smegmatis. Foam cells can also be generated by treatment with isolated lipids. Trehalose dimycolate isolated from the
cell wall of M. bovis or Calmette–Guérin (BCG) bacilli binds
to macrophage receptor with collagenous structure (MARCO)
and is internalised by the action of TLR2, thereby leading to
foam cell formation. Because trehalose dimycolate is released
and captured by infected cells, a large number of macrophages in
the lesion become foam cells (Rhoades et al., 2003) (Figure 3).
Foam cells are also generated in other infections, such as those
caused by Toxoplasma and Chlamydia (Portugal et al., 2008). See
also: Immune Mechanisms against Intracellular Pathogens;
Tuberculosis: Immunity
Electron microscopy has shown that M. tuberculosis is in contact with lipid bodies within foam cells. Interestingly, M. tuberculosis can also survive in adipocytes, cells that store lipids in
the adipose tissue. Moreover, lipid inclusions have been found
inside the bacilli themselves. Indeed, these bacteria can catabolise
cholesterol (Pandey and Sassetti, 2008) and the growth of experimental bacterial strains deficient in cholesterol transporters is
hindered in conditions where cholesterol is the source of carbon.
Taken together, all these observations suggest that the pathogen
uses lipids from the host as a nutrient. Therefore, the pathogen
meets nutritional advantages by living within cells that accumulate lipids. This strategy may allow the bacilli to remain in a
dormant non-replicative state (Peyron et al., 2008).
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
7
Macrophage Foam Cells
Mycobacterium
tuberculosis
Multivesicular
bodies exocytosed TLRs
SR (MARCO)
Granuloma
Internalization
TDM
Macrophage
Foam cell
Noninfected
macrophage
(a)
TNFα IL-1 IL-6
iNOS COX2
Foam cell
IL-12
AP-1
NFκB
STAT1
TH1
IFN-γR
IFNγ
(b)
PPAR
Infected
macrophage
TH1 lymphocyte
TLRs
TH1 lymphocyte Bacterial pathogens
Macrophage
Figure 3 Foam cell formation in the granuloma during the infection with Mycobacterium tuberculosis. (a) Bacilli that reside within macrophages overproduce
lipids such as trehalose dimycolates (TDM) that consolidate as multi-vesicular bodies and are subsequently exocytosed to the extracellular milieu. Through
the SRs and TLRs exocytosed bodies are taken up by macrophages that then become foam cells. (b) Cross-talk between macrophages and TH 1 lymphocytes.
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9
Macrophage Foam Cells
Further Reading
Chinetti-Gbaguidi G and Staels B (2009) Lipid ligand-activated transcription factors regulating lipid storage and release in human
macrophages. Biochimica et Biophysica Acta 1791: 486–493.
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10
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and the progression of the human tuberculosis granuloma. Nature
Immunology 10: 943–948.
Silverstein RL (2009) Inflammation, atherosclerosis, and arterial
thrombosis: role of the scavenger receptor CD36. Cleveland Clinic
Journal of Medicine 76 (Suppl 2): S27–S30.
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