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Foam cells are lipid-loaded macrophages that are of established atherosclerotic plaques. Thus, foam cells are
generated from the massive uptake of modified considered therapeutic targets for the treatment of atherosclerosis
low-density lipoproteins and the intracytoplas- (Saha et al., 2009). These cells have also been detected in other
matic accumulation of cholesteryl esters. Foam forms of chronic inflammation, including septic arthritic lesions
cells are present in all stages of atherosclerosis and in tissues infected by persistent pathogens such as Mycobac-
terium, Chlamydia and Toxoplasma (Portugal et al., 2008).
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 Macrophages
Mycobacterium, Chlamydia and Toxoplasma. These
pathogens meet nutritional advantages by resid- Macrophages play a critical role in tissue homeostasis and
ing within cells that accumulate lipids. When the immunity. The use of multicolour fluorescence-activated cell
immune system is unable to eliminate substances sorting together with adoptive transfer of precursors has helped
perceived as foreign, it produces a granuloma, characterise in vivo differentiation of macrophage populations.
composed mostly of macrophages, attempting to Like many other cells in the immune system, blood mono-
wall off the non-self material. This article reviews cytes and many macrophage subsets originate from pluripotent
the processes that lead to the regulation of foam haematopoietic stem cell within the bone marrow. Successive
cell formation in atherosclerosis and infection. commitment steps generate macrophage/dendritic cell progeni-
tors 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
Introduction these cells are short-lived. Under normal conditions, a few of
these monocytes (patrolling monocytes) enter tissues and dif-
In the mid-nineteenth century, Rudolf Virchow postulated that ferentiate into macrophages. Recently, it has been shown that
cellular pathology is critical in atherosclerosis (reviewed by in many tissues (i.e. brain, skin and liver) resident macrophage
Mayerl et al., 2006). However, only in recent years has the inflam- populations derive from yolk sac precursors that colonise their
matory process leading to atherosclerosis been characterised. target tissues during embryogenesis and form stable networks
Today, we know that foam cells are lipid-laden macrophages within these tissues by differentiation in situ. Such macrophage
present in all stages of atherosclerosis. Foam cells play a major populations self-renew in the steady state and do not depend
role in the formation of the fatty-streak, the earliest pathological on continuous replacement by the bone marrow (reviewed by
sign of atherosclerosis, and in the progression and pathogenicity Ginhoux and Jung, 2014). Depending on the specific loca-
tion, resident macrophages are given different names that may
eLS subject area: Cell Biology be associated with specialised functional activities (e.g. osteo-
How to cite:
clasts in the bone, alveolar macrophages in the lung, histiocytes
Valledor, Annabel F; Lloberas, Jorge; and Celada, Antonio in the connective tissue, mesangial cells in the kidney, sinu-
(February 2015) Macrophage Foam Cells. In: eLS. John Wiley & soidal lining cells in the spleen, microglia in the brain, Kupffer
Sons, Ltd: Chichester. cells in the liver and Langerhans cells in the skin). See also:
DOI: 10.1002/9780470015902.a0020730.pub2 Macrophages
Macrophages are approximately 21 μm in diameter and 2009). Macrophages also control lipid metabolism, as described
can be identified by the specific expression of a number later. See also: Spleen
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 activ- Macrophages and Inflammation
ities inside and outside the immune system. The initial function
that was associated with these cells is phagocytosis, which is Nowadays, we know that inflammation represents a major factor
the capacity to engulf and digest pathogens, cellular debris and in the development of a number of chronic diseases, such as can-
apoptotic bodies (Paidassi et al., 2009). Phagocytosis is part of cer, metabolic syndrome, autoimmunity and neurodegenerative
the non-specific immune defence response (or innate immunity). disorders. For this reason, many novel strategies for therapeutic
After the pathogen is recognised as foreign material by specific intervention of several chronic diseases aim at interfering with
pathogen-associated molecular pattern receptors, the phagocytic the inflammatory process, and in particular, with the activities of
cell makes temporary extensions of the cell membrane to sur- macrophages.
round the pathogenic particle and internalise it within vacuoles The expression of selected surface molecules allows us to
(phagosomes). Phagosomes then fuse with lysosomes to make distinguish among different monocyte subsets in circulation. In
phagolysosomes, in which a number of enzymes and other humans, expression of CD16 (also known as Fc-gamma recep-
toxic products destroy the microorganisms (Flannagan et al., tor III, FcγRIII) distinguishes two monocyte subsets. Most of
2009). ‘Foreign’ proteins derived from these microorganisms the circulating monocytes (80–90%) are CD14+ /CD16− cells
are hydrolysed, thus generating peptides (small fragments of that express high levels of the chemokine receptor CCR2 and
proteins). Part of these peptides is released to the extracellular low levels of CX3CR1. These monocytes are poor producers
medium as waste. Released peptides can then be recognised of inflammatory cytokines and they preferentially release the
by B lymphocytes through their surface immunoglobulins, a anti-inflammatory cytokine IL-10. Conversely, CD16+ mono-
process that leads to B lymphocyte activation. Some of the cytes express high levels of CX3CR1 and low levels of CCR2
protein fragments are further processed into short peptides inside and account for inflammatory cytokine production. In the mouse,
macrophages (10–14 amino acids in length) and are inserted monocyte subsets can be distinguished on the basis of the expres-
into the antigen-presenting groove of major histocompatibility sion of the Ly6C antigen and of the chemokine receptors CCR2
complex (MHC) molecules for subsequent export to the cell and CX3CR1. Ly6C− monocytes patrol blood vessels under
membrane. These peptide–MHC complexes are then presented steady-state conditions, whereas monocytes that express Ly6C
to T lymphocytes through a process known as antigen presen- and high levels of CCR2 are recruited at sites of inflammation
tation. If the interacting T lymphocyte displays the appropriate and in lymph nodes and secrete large amounts of inflammatory
T cell receptor (TCR) for the peptide–MHC combination, the T cytokines (Geissmann et al., 2003; Mantovani et al., 2009). When
lymphocyte will be activated and stimulated to release cytokines inflammation takes place, the bone marrow generates Ly6C+
that modulate the immune response (Hume, 2008). These are monocytes that strongly interact with endothelial cells lining the
the early events of the specific immune defence (or adaptive blood vessels at the inflammatory loci and then enter the dam-
immunity). With the coordinated action of T and B lymphocytes, aged tissue through a process known as extravasation, where they
the process of antigen presentation may result in the production undergo the morphological and functional changes that lead to
of specific antibodies that attach to antigens on the surface of differentiation into activated tissue macrophages.
pathogens (opsonisation). Opsonised particles are more effi- During the initial phases of the inflammatory process and in
ciently recognised by macrophages, thus resulting in enhanced response to several cytokines (e.g. interferon γ, IFNγ) or bacterial
phagocytosis and clearance of the foreign particles. See also: products such as lipopolysaccharide (LPS), macrophages become
Phagocytosis; Phagocytosis: Enhancement ‘classically activated’ and exert strong pro-inflammatory activi-
During the immune response, macrophages are also involved ties through the release of a number of toxic compounds such as
in the production of pro-inflammatory mediators, including nitric oxide (NO) and reactive oxygen species (ROS). During the
enzymes, nitrogen and oxygen reactive species, complement progression of inflammation, macrophages phagocytose apop-
proteins and cytokines that control the functional activity of totic bodies derived from neutrophils, macrophages or other cells
other cells. For example, the cytokines tumour necrosis factor present at the inflammatory site. Extensive phagocytosis makes
α (TNFα) and interleukin-1 beta (IL-1β) released by activated macrophages switch phenotype to become anti-inflammatory
macrophages act in the hypothalamus to induce fever. Over- cells with active roles in tissue repair (Arnold et al., 2007). See
production of these cytokines during septic shock can lead to also: Inflammatory Mediators
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
Conversion of Macrophages into
surface markers that are expressed on aged red blood cells. After Foam Cells
phagocytosis of these cells, some of their contents are recycled,
including iron molecules, and later released by macrophages to Macrophages play a major role in lipoprotein homeostasis.
the plasma depending on the needs of the organism to produce Under normal conditions, macrophages take up low-density
more red blood cells in the bone marrow (Beaumont and Delaby, lipoproteins (LDLs) through LDL receptors (LDLRs). After
internalisation, LDL particles are degraded in the lysosomal recruitment into the vessel wall (Figure 1). Under the effect of
compartment, where enzymes hydrolyse cholesteryl esters to oxLDL, endothelial cells express adhesion molecules, including
free cholesterol and fatty acids. Free cholesterol is toxic and E- and P-selectins, which interact with integrins expressed on
needs to be re-esterified into cholesteryl esters for storage as lipid the surface of circulating monocytes, thus facilitating monocyte
droplets in the cytoplasm. The dynamic balance between the tethering and rolling on the endothelial layer. This process
amount of free cholesterol and cholesteryl esters within the cell is is followed by firm adhesion of monocytes on endothelial
regulated by two enzymes located in the endoplasmic reticulum: cells mediated by endothelial expression of vascular adhesion
acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) and molecule-1 (VCAM-1) and intercellular adhesion molecule-1
neutral cholesterol ester hydrolases (nCEH) (reviewed by Li (ICAM-1). Finally, transmigration through the endothelium
and Palinski, 2006). In normal conditions, free cholesterol and involves the interaction of junctional adhesion molecules (JAM)
phospholipids are mobilised to the plasma membrane by adeno- and connexins (reviewed by Galkina and Ley, 2007).
sine triphosphate-binding cassette (ABC) transporters, including Endothelial transmigration of monocytes is also promoted
ABCA1 and G1, and subsequently transferred to exogenous by chemokines, such as monocyte chemoattractant protein 1
apolipoprotein acceptors that make up high-density lipoproteins (MCP-1) and Ccl5 (also known as Rantes) (Figure 1). The
(HDLs). This process is known as cholesterol efflux and it is chemokine C-C receptors CCR2 and CCR5 are expressed in
the first step in reverse cholesterol transport from peripheral monocytes and play an important role in atherosclerosis by bind-
tissues to the liver. Human genetic deficiency in ABCA1 leads ing to MCP-1 and Ccl5, respectively. Genetic manipulation of
to Tangier disease, a condition characterised by severe HDL these chemokine/receptor systems have been shown to affect
deficiency, the accumulation of foam cells in many tissues and plaque size and progression (reviewed by Gautier et al., 2009).
an increased susceptibility to develop atherosclerosis (reviewed Macrophage migration inhibitory factor (MIF) is a cytokine that
by Takahashi et al., 2005). plays a regulatory role in monocyte adhesion and migration and
Each of the lipid constituents of LDL, including cholesteryl in macrophage proliferation. Increased expression of MIF has
esters, phospholipids, sterols and triglycerides, can undergo oxi- been demonstrated in human atherosclerotic lesions, whereas the
dation. Under conditions that lead to the accumulation of oxidised absence of the gene encoding MIF reduces atherosclerosis in
LDL (oxLDL) or other forms of modified LDL, macrophages mice (reviewed by Noels et al., 2009). See also: Atherosclerosis:
become highly efficient at taking up these particles through the Pathogenesis, Clinical Features and Treatment
action of scavenger receptors (SR)-A, −BI and CD36, which Once monocytes have taken residence in the arterial
have evolved as molecular pattern recognition receptors to medi- wall intima, they undergo phenotypic transformation into
ate phagocytosis of pathogens and apoptotic cells (reviewed macrophages, internalise large amounts of modified LDLs via
by Hazen, 2008). The accumulation of LDL derivatives inside scavenger receptors and become foam cells, as described earlier
macrophages inhibits the surface expression of classical LDLRs (Figure 1). This is the initial step in formation of the fatty streak
but not of scavenger receptors (Brown and Goldstein, 1986). in the arterial wall. Thus, a common strategy in reducing the risk
Thus, macrophages conserve the capacity to accumulate very of atherosclerosis is currently based on lowering LDL levels in
large amounts of oxLDL-derived lipids and become lipid-loaded the organism through the use of statins, inhibitors of HMG-CoA
foam cells. See also: Macrophages in Lipid and Immune reductase, the rate-limiting enzyme involved in the cholesterol
Homeostasis biosynthetic pathway. By reducing the cellular capacity to
synthesise cholesterol, LDLRs are upregulated, particularly in
hepatocytes, and they remove the circulating pro-atherogenic
Macrophages in the Development LDL particles more rapidly (Brown and Goldstein, 1986).
During progression of the atherosclerotic plaque, invading
of Atherosclerotic Lesions macrophages and newly formed foam cells secrete ROS and the
enzyme 12/15-lipoxygenase (LO) that contributes to enhanc-
Atherosclerotic lesions arise in the arterial wall, typically at ing the oxidation of LDL particles. Foam cells also release
vessel bifurcations that are exposed to non-laminar blood flow. pro-inflammatory cytokines (including TNF-α, IL-1β and IL-6),
The intima, the arterial layer adjacent to the lumen, consists chemokines, growth factors, such as platelet-derived growth
of a monolayer of endothelial cells and an internal elastic tis- factors (PDGFs), endothelial-derived growth factor (VEGF)
sue, which, in humans, is rich in proteoglycans, particularly and insulin-like growth factors (IGFs), and enzymes, such as
near branch sites. Lipid accumulation is generally absent from cysteine-, serine- and metallopeptidases, which degrade extra-
healthy intima, as are macrophages, except for occasional cellular matrix components (reviewed by Saha et al., 2009).
patrolling monocytes. Underneath the intima, a thick arterial The combined action of all these molecules enhances the
media, consisting mainly of smooth muscle cells interwoven inflammatory process, allowing T lymphocytes, natural killer
with elastin and collagen fibres, conveys mechanical stability cells, dendritic cells and mast cells to infiltrate the vascular
to the arterial wall (reviewed by Li and Palinski, 2006). The subendothelium. Furthermore, the proliferation and migration of
accumulation of lipids in the arterial intima is dependent on smooth muscle cells into the intima facilitates the establishment
the interaction of LDL particles with proteoglycans within the of the atherosclerotic plaque.
extracellular matrix. LDL particles may then undergo modifi- At later stages of atherosclerosis, foam cells express high lev-
cation (e.g. oxidation) by endothelial and other arterial cells els of cycloxygenases (COX)-1 and -2 (reviewed by Cipollone
and initiate an inflammatory process that promotes monocyte et al., 2008). These are enzymes that generate pro-inflammatory
(a) (b)
Adhesion
VCAM-1
Vascular
lumen
P-selectin Monocyte
E-selectin
Migration ICAM-1
MCP-1
CS-1
CCR-2
ox LDL
LDL Endothelial
cells
Extracellular HDL
Homeostatic
matrix LDL oxidation responses
Differentiation mmLDL 15 LO apo E
M-CSF iNOS ABC-1
ACAT
Intima
Proinflamatory ox LDL
process
TNF-α
IL-1β ox LDL uptake Foam cell
IL-6 CD36
Internal elastic lamina Macrophage SR-A
Media
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 erosion and rupture by forming a surface on which activated
vasoconstriction and platelet aggregation. Inflammatory medi- platelets may initiate thrombosis and amplify inflammation,
ators also activate resident cells in the lesion and the secretion thereby leading to stroke and myocardial infarction. See also:
of proteolytic enzymes by macrophages contributes to plaque Cholesterol and Vascular Disease
Transcriptional Control to Prevent response element binding protein (SREBP)-1c, which in turn
triggers the expression of enzymes involved in fatty acid syn-
Foam Cell Formation and the thesis and desaturation and triglyceride formation (Repa et al.,
Development of Atherosclerosis 2000). In macrophages, positive regulation of fatty acid biosyn-
thesis and their use in cholesterol sterification may reflect an
Liver X receptors (LXRs) and peroxisome proliferator-activated adaptive mechanism provided by LXRs to buffer the toxic effects
receptors (PPARs) are ligand-dependent transcription factors that of free cholesterol (Tabas, 2002). Moreover, desaturation of fatty
belong to the nuclear receptor family. LXRs and PPARs posi- acids may provide the cell with ligands for other nuclear recep-
tively regulate gene expression by binding as heterodimers with tors, including PPARs (see later discussion). The finding that
other members of the nuclear receptor family, the retinoid X lipogenesis is strongly activated by available synthetic LXR ago-
receptors (RXRs), to specific response elements on the promoter nists limits their potential use as anti-atherogenic drugs. However,
or enhancer regions of their target genes. Several studies sug- it may be possible to develop novel ligands that differentially
gest that LXRs and PPARs play critical roles in feed-forward regulate programs of gene expression involved in cholesterol
mechanisms that regulate cholesterol and fatty acid homeosta- efflux and fatty acid biosynthesis. In the absence of activating
sis in macrophages in response to rapid changes in cellular lipids ligands, LXR/RXR heterodimers actively repress target genes
(reviewed by Ricote et al., 2004). by binding nuclear receptor co-repressors such as NCoR and
Two isoforms of LXR have been identified, LXRα and β, SMRT. In LXR-deficient macrophages, NCoR is not recruited to
both of which are activated by oxidised derivatives of choles- LXR target genes, which leads to derepression of the ABCA1
terol (oxysterols) (Repa and Mangelsdorf, 2000). Treatment gene and enhanced cholesterol efflux, but does not result in
of cells with oxLDL leads to LXR activation, which suggests increased expression of SREBP1c or increased fatty acid biosyn-
that LXR-activating oxysterols are present in oxLDL. LXR thesis (Wagner et al., 2003). Therefore, the generation of selective
agonists induce in vitro cholesterol efflux from macrophages to LXR modulators that disrupt the binding of LXR to co-repressors
extracellular apoAI acceptors and inhibit the development without leading to co-activator recruitment may provide a strat-
of atherosclerosis in mice. Moreover, the transplantation egy to selectively increase ABCA1 expression in macrophages
of LXR-deficient bone marrow progenitor cells into either and thus be used for anti-atherogenic purposes without having
apolipoprotein E (apoE)-deficient or LDLR-deficient mice leads side effects on lipogenesis.
to an increase in atherosclerotic lesions, thereby suggesting that Within the PPAR subfamily, three isoforms have been identi-
activation of the LXR pathway exerts protective roles that impede fied, namely PPARα, 𝛿 and γ. PPARs bind a broad range of fatty
the accumulation of excess cholesterol within cells and also pre- acids and their metabolites. While there is some preference for
vent foam cell formation and the development of atherosclerosis specific fatty acids by each PPAR, when present at sufficiently
(Tangirala et al., 2002). In fact, LXR–RXR heterodimers directly high concentrations many fatty acids are capable of activating
upregulate the expression of a number of genes involved in lipid
all three PPAR isoforms. PPARs can be also activated by certain
and lipoprotein homeostasis, such as the cholesterol transporters
eicosanoids, which are produced by metabolism of arachidonic
ABCA1 and G1, phospholipid transfer protein (PLTP) and apoE
acids and other long-chain polyunsaturated fatty acids (reviewed
(Figure 2) (reviewed by A-González and Castrillo, 2011). All
by Menendez-Gutierrez et al., 2012). PPARα is also the molecu-
these molecules participate in promoting cholesterol efflux, thus
lar target of fibrates, such as gemfibrizol, which are used clin-
preventing and/or reducing cholesteryl ester accumulation in
ically to treat hypertriglyceridaemia. Indeed, PPARα regulates
arterial wall macrophages. Moreover, the recognition of apoE
the production of enzymes involved in fatty acid β-oxidation
as part of chylomicron remnants, very low-density lipopro-
and lipoprotein metabolism. Clinical trials examining the effects
teins (VLDLs) and intermediate density lipoproteins (IDLs) by
LDLRs facilitates hepatic uptake of lipoprotein remnants. of fibrates in primary and secondary cardiovascular prevention
LXR activation also leads to the coordinated upregulation studies demonstrated a significant reduction in coronary heart dis-
of other apolipoproteins (apoC-I, apoC-IV and apoC-II) and ease, with highest efficacy in overweight individuals with insulin
lipoprotein lipase (LPL), which affect lipoprotein metabolism resistance and chronic inflammation (reviewed by Bouhlel et al.,
(Mak et al., 2002). For example, ApoC-II is the obligate cofactor 2008).
for LPL and is required for LPL-dependent hydrolysis of triglyc- PPARγ is activated by thiazolidinediones (TZDs), such as
erides present in chylomicrons, VLDLs and HDLs. Deficiency rosiglitazone, which act as insulin sensitisers and have been used
of apoC-II results in hypertriglyceridaemia (Fojo and Brewer, in the treatment of type 2 diabetes mellitus. Oxidised lipids
1992). present in oxLDL, such as 15-hydroxyeicosatetraenoic acid and
More recent studies have also demonstrated that LXR activa- 13-hydroxyoctadecadienoic acid, also have the capacity to acti-
tion leads to increased expression of Mylip/Idol, an E3-ubiquitin vate PPARγ (reviewed by Ricote et al., 2004). The scavenger
ligase that promotes degradation of several members of the LDLR receptor CD36, involved in oxLDL uptake, is a PPARγ target
family. Therefore, the LXR pathway not only enhances mecha- gene (Figure 2). However, despite increased CD36 expression,
nisms involved in cholesterol efflux but also participates in limit- TZDs do not induce significant cellular cholesterol accumula-
ing the uptake of circulating LDL by macrophages and other cells tion (Moore et al., 2008). Indeed, PPARγ agonists reduce carotid
(Zelcer et al., 2009; Hong et al., 2010). artery wall thickening in diabetic patients and direct evidence that
Apart from their role in reverse cholesterol transport, LXR PPARγ exerts anti-atherogenic action has been shown in murine
agonists induce the expression of the transcription factor sterol models of atherosclerosis (reviewed by Li and Palinski, 2006).
Triglyceride-rich oxLDL
lipoproteins apoptotic cells
LPL
CD36 SRs
Oxysterols
PLA2 FAS
Cholesterol efflux
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 sys- et al., 2002). Microarray analysis suggests that most PPARγ tar-
tem of LDLR-deficient mice with PPARγ-null bone marrow pro- get genes, such as CD36, apoE, adipose differentiation-related
genitor cells results in increased atherosclerosis (Chawla et al., protein (ADRP), ABCG1, the peroxisomal enzymes Ech1 and
2001). There are several points of cross-talk between PPARs and Pex11a, α mannosidase II and carnitine palmitoyl transferase
LXRs in the regulation of cholesterol homeostasis. PPARα and γ (Cpt1), participate in lipid transport and metabolism. Interest-
ingly, some of the target genes for PPARγ are also induced by
induce the expression of ABCA1 and stimulate cholesterol efflux
PPAR𝛿 ligands, suggesting that these two isoforms have overlap-
in human primary and THP-1 macrophages through a transcrip- ping transactivator functions in macrophages (reviewed by Ricote
tional cascade mediated by LXRα (Chawla et al., 2001; Chinetti et al., 2004).
et al., 2001). Consistent with these findings, basal cholesterol In addition to the regulation of lipid metabolism, LXRs and
efflux from cholesterol-loaded macrophages to HDL is signif- PPARγ exert both overlapping and specific repressive actions
icantly reduced after disruption of the PPARγ gene (Akiyama on transcriptional programs induced during the macrophage
Mycobacterium
tuberculosis
Multivesicular
Granuloma
bodies exocytosed TLRs
SR (MARCO)
Internalization
TDM
Macrophage
Foam cell
Noninfected
(a) macrophage
iNOS COX2
IL-12 Foam cell
AP-1
NFκB Infected
TH1 STAT1 macrophage
IFN-γR
PPAR
TH1 lymphocyte
IFNγ TLRs
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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