Download Role and function of macrophages in the metabolic syndrome

Biochem. J. (2012) 442, 253–262 (Printed in Great Britain)
253
doi:10.1042/BJ20111708
REVIEW ARTICLE
Role and function of macrophages in the metabolic syndrome
Prerna BHARGAVA and Chih-Hao LEE1
Department of Genetics and Complex Diseases, Department of Nutrition, Division of Biological Sciences, Harvard School of Public Health, 665 Huntington Ave, Boston,
MA 02115, U.S.A.
Macrophages are key innate immune effector cells best known
for their role as professional phagocytes, which also include
neutrophils and dendritic cells. Recent evidence indicates that
macrophages are also key players in metabolic homoeostasis.
Macrophages can be found in many tissues, where they
respond to metabolic cues and produce pro- and/or antiinflammatory mediators to modulate metabolite programmes.
Certain metabolites, such as fatty acids, ceramides and cholesterol
crystals, elicit inflammatory responses through pathogensensing signalling pathways, implicating a maladaptation of
macrophages and the innate immune system to elevated metabolic
stress associated with overnutrition in modern societies. The
outcome of this maladaptation is a feedforward inflammatory
response leading to a state of unresolved inflammation and a
collection of metabolic pathologies, including insulin resistance,
fatty liver, atherosclerosis and dyslipidaemia. The present
review summarizes what is known about the contributions of
macrophages to metabolic diseases and the signalling pathways
that are involved in metabolic stress-induced macrophage
activation. Understanding the role of macrophages in these
processes will help us to develop therapies against detrimental
effects of the metabolic syndrome.
INTRODUCTION
system, especially macrophages, to respond in a deleterious
manner, in which a resolution state could not be achieved [7,8]. At
around the same time as these studies were occurring, researchers
observed that insulin resistance and hyperglycaemia led to dysregulated immune responses and increased incidences of infection
in patients with the metabolic syndrome [9–16]. Together, it has
become evident that metabolic pathways are tightly intertwined
with inflammatory signalling and immune responses.
As environmental sentries, it is not surprising that macrophages
sense and regulate metabolism. This link between macrophages
and metabolic regulation was strengthened further with the discovery of resident macrophage populations in metabolically active
tissues, such as WAT (white adipose tissue) and liver [17,18]. The
interplay between resident macrophages and pathologies associated with the metabolic syndrome has been studied extensively
since. In the present review, we highlight major contributions
of macrophages to the metabolic milieu and describe how the
functions of macrophages are altered during states of metabolic
dysfunction. We begin with a brief overview of the recruitment
of macrophages in various metabolic tissues and the diseases
associated with their activation. We then discuss some proposed
mechanisms for the inflammatory pathways that lead to pathologies, with an emphasis on insulin resistance/Type 2 diabetes.
The innate immune system, which consists of macrophages,
dendritic cells and a variety of other effector cells, has evolved
as a formidable defence against external threats to the human
host. When first described by Élie Metchnikoff in the late 1800s,
macrophages were thought to primarily function as phagocytes.
In the next several decades, intense effort went into understanding
the mechanisms that led to macrophage activation. It was not until
about 100 years later that researchers first started to document the
innumerable roles that macrophages play [1]. We now know that
macrophages are found throughout the body and are involved in
tissue homoeostasis, wound healing, general surveillance of host
threats and, as was first observed, killing of foreign pathogens.
Abundant sources of food that have high energy content
and are enriched in saturated fats, coupled with a lack of
physical activity, are responsible for the sharp increase in a
collection of pathologies, such as obesity, hepatosteatosis, insulin
resistance and atherosclerosis, known as the metabolic syndrome.
All of these pathologies increase the chance of developing
cardiovascular disease, diabetes mellitus and premature death
[2]. The observation that anti-inflammatory salicylates could
improve insulin sensitivity and glucose responsiveness gave the
first indication that metabolic syndrome is associated with lowgrade chronic inflammation [3]. This was followed by reports that
inflammatory cytokines, such as TNFα (tumour necrosis factor
α), inhibit insulin responsiveness in adipocytes, providing a link
between inflammation and metabolic pathways [4–6]. Subsequent
studies have suggested that lipid overload triggers the immune
Key words: inflammatory signalling, insulin resistance, macrophage activation, metabolic disease, metabolic syndrome, white
adipose tissue inflammation.
AN ESSENTIAL ROLE FOR MACROPHAGES IN METABOLIC
PATHOLOGIES
Resident macrophages in different tissues adapt to their
local microenvironment and exhibit diverse functional and
Abbreviations used: ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain; ATM, adipose-tissue-resident
macrophage; BAT, brown adipose tissue; CCR2, CC chemokine receptor 2; CHOP, C/EBP (CCAAT/enhancer-binding protein)-homologous protein;
DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; GPCR, G-protein-coupled receptor; HIF, hypoxia-inducible factor;
IFNγ, interferon γ; IKK, inhibitor of nuclear factor κB kinase; IL, interleukin; IRS-1, insulin receptor substrate-1; JNK, c-Jun N-terminal kinase; LDL,
low-density lipoprotein; Ldlr, LDL receptor; LXR, liver X receptor; MCP-1, monocyte chemoattractant protein 1; miRNA, microRNA; mTOR, mammalian
target of rapamycin; NAFLD, non-alcoholic fatty liver disease; NF-κB, nuclear factor κB; NLRP3, NLR (nucleotide-binding-domain- and leucine-rich-repeatcontaining) family, pyrin-domain-containing 3; oxLDL, oxidized LDL; PKR, double-stranded RNA-dependent protein kinase; PPAR, peroxisome-proliferatoractivated receptor; STAT6, signal transducer and activator of transcription 6; SVF, stromal vascular fraction; TLR, Toll-like receptor; TNFα, tumour necrosis
factor α; UPR, unfolded protein response; WAT, white adipose tissue.
1
To whom correspondence should be addressed (email [email protected]).
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P. Bhargava and C.-H. Lee
signalling molecules in metabolic diseases. Earlier studies
have demonstrated that MCP-1- and CCR2-knockout mice are
protected from atherosclerosis [19–21]. CCR2-knockout mice
also display attenuated macrophage accumulation and chronic
inflammation in adipose tissue [22]. In addition, mice lacking
MCP-1 or expressing a dominant-negative form of MCP-1 show
improved insulin sensitivity [23], whereas transgenic MCP-1
overexpression in adipose tissue causes insulin resistance and
hepatic steatosis [23,24]. Other chemokines, such as osteopontin,
angiopoietin-like protein 2 and CXCL14 (CXC chemokine ligand
14) have also been shown to play a role in obesity-induced
macrophage recruitment [25–28]. These studies demonstrate that
macrophage infiltration is an essential step for metabolic disease
pathogenesis.
Activation
Figure 1 Metabolic dysregulation leads to a feedforward cycle of chronic
inflammation
Activation of inflammatory pathways by metabolic stress leads to macrophage recruitment
to sites of affected tissues, such as vasculature, WAT, muscle and liver. There, they pick up
excess lipids and cell debris in an attempt to restore homoeostasis. The presence of persistent
pro-inflammatory stimulants (e.g. fatty acids and cholesterol) causes macrophage dysfunction,
including defective efferocytosis and unresolved inflammation, resulting in recruitment and
activation of more macrophages. In WAT, infiltrated macrophages are concentrated around the
dying fat cells, known as the crown-like structure. In the vasculature, macrophages are enriched
in areas of fatty streaks. Inflammatory cytokines produced by activated macrophages induce
insulin resistance in major metabolic tissues, promote hepatosteatosis and facilitate foam cell
and plaque formation in the vessel wall.
morphological phenotypes. Resident populations, such as Kupffer
cells in the liver, resident macrophages in WAT and alveolar
macrophages in the lung, show expression profiles distinct
from those of recruited macrophages responding to systemic
cues [1]. For example, studies have demonstrated that ATMs
(adipose-tissue-resident macrophages) are functionally distinct
from infiltrating macrophages (discussed below). In the process
of understanding the aetiology of the metabolic syndrome, we
have begun to understand the general mechanisms underlying
metabolic diseases, particularly the roles of macrophages in
atherosclerosis and in adipose tissue insulin resistance. Owing to
a lack of specific markers for resident and recruited macrophages
and the cross-talk between tissues in the progression of
metabolic diseases, it is often difficult to tease apart the precise
contribution of individual macrophage populations to the onset
and development of systemic metabolic dysfunction. Nonetheless,
it is clear that the interaction between macrophages and metabolic
cells plays a key role in disease pathogenesis. Macrophages are
recruited by pro-inflammatory cytokines and chemokines to deal
with lipid overload-induced tissue dysfunction and are also subject
to the detrimental effect of lipid influx. As such, metabolic stress
initiates a feedforward cycle of inflammatory responses, resulting
in a state of unresolved chronic inflammation, with macrophages
as major culprits contributing to metabolic diseases (Figure 1).
Macrophage infiltration and activation
Recruitment
The production of chemokines, the factors that recruit immune
cells to sites of trouble, is increased in states of metabolic
dysfunction. MCP-1 (monocyte chemoattractant protein 1) [also
known as CCL2 (CC chemokine ligand 2)] and its receptor CCR2
(CC chemokine receptor 2) are the most studied chemokine
c The Authors Journal compilation c 2012 Biochemical Society
Macrophages respond to many different types of foreign and
host-derived stimuli and exhibit very precise and co-ordinated
activation states according to the signals they receive. These states
lie on a spectrum ranging from the pro-inflammatory state to the
anti-inflammatory state [29] (Figure 2). Foreign pathogens or Th1
cytokines [e.g. TNFα, IL (interleukin)-1β and IFNγ (interferon
γ )] transduce signals that activate macrophages to a proinflammatory phenotype, typically referred to as an M1 response,
characterized by the expression of inflammatory markers, such
as TNFα, IFNγ and iNOS (inducible nitric oxide synthase) [29].
In contrast, M2 macrophages, induced by Th2 cytokines IL-4
and IL-13, produce anti-inflammatory mediators, notably IL-10
[29]. As discussed below, the M1/M2 paradigm also applies
to metabolic regulation, with M1 inducing and M2 preventing
metabolic diseases respectively (Figure 3). Interestingly, dietary
fatty acids are able to polarize macrophages towards M1 or M2
activation states, depending on the signalling molecules with
which they interact (Figure 2), thus providing a molecular basis
for the cross-talk between metabolic and inflammatory pathways.
Resolution/deactivation
The initial pro-inflammatory response is terminated by antiinflammatory cytokines, such as IL-10, which is induced by both
M1 and M2 cytokines to deactivate macrophages and promote
resolution [30–33]. Lack of this termination signal leads to
persistent establishment of the inflammatory response [34–36].
Epidemiological studies have shown that polymorphisms in the
IL10 gene are associated with obesity and metabolic diseases [37–
39]. Furthermore, in patients with Type 2 diabetes, circulating
monocytes express decreased levels of IL-10 [40]. IL-10 and
other deactivating signalling molecules are also induced during
efferocytosis, a process by which macrophages engulf and clear
apoptotic cells in an effort to prevent necrosis and suppress
inflammation [41]. This process is thought to help remove
oxidized lipids and cholesterol and to activate Akt and NF-κB
(nuclear factor κB) survival pathways [42]. Several studies have
shown that efficient efferocytosis is necessary to inhibit necrotic
plaque formation and defects in efferocytosis lead to the formation
of unstable lesions and an increase in systemic inflammation [43–
46]. Faulty efferocytosis has also been observed in diabetic mouse
models and is thought to promote inflammatory signalling [47].
Oxidative stress and macrophage insulin resistance are two of the
potential mechanisms that cause defective efferocytosis [41,48].
Therefore the combined effects of persistent pro-inflammatory
stimulation from increased lipid influx, decreased deactivating
signals and compromised efferocytosis lead to the unresolved
inflammation in metabolic dysregulation.
Role and function of macrophages in the metabolic syndrome
Figure 2
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Dietary lipids and inflammatory mediators share common signalling pathways in the control of macrophage activation
The Th2 (M2) type response, elicited by Th2 cytokines, notably IL-4 and IL-13, and parasitic worm infection, induces an anti-inflammatory phenotype in the macrophage and promotes metabolic
homoeostasis, tissue repair, wound healing and angiogenesis. STAT6 is activated by Th2 cytokines to control the expression of PPARδ and PPARγ . Together, they regulate mitochondrial oxidative
metabolism and macrophage alternative activation. The ω − 3 fatty acids DHA and EPA are known to ligate the GPCR GPR120 to promote anti-inflammatory response. These fatty acids can also
mediate PPAR activation. In contrast, saturated fatty acids (FAs), ceramides (metabolites of fatty acids) and cholesterol crystal can induce pro-inflammatory activation of the macrophage through
pathogen-sensing proteins TLR2/TLR4, which activate the JNK cascade, leading to NF-κB relocation to the nucleus and induction of inflammatory cytokines and glycolytic pathways. Excess lipids
have also been shown to induce ER stress and inflammasome activation. Pro-inflammatory cytokines produced by these macrophages, including TNFα and IL-1β, cause tissue damage and inhibit
insulin signalling, which contribute to the pathogenesis of metabolic diseases. IκB, inhibitor of NF-κB; iNOS, inducible nitric oxide synthase.
Figure 3
Cross-talk between macrophages and adipocytes plays an important role in adipose tissue homoeostasis
In the physiological state, ATMs exhibit an M2 phenotype, mediated by the Th2 cytokines IL-4 and IL-13, and downstream transcription factors STAT6 and PPARδ/PPARγ . Several cell types within
WAT have been reported to be the sources of Th2 cytokines, including T-lymphocytes, eosinophils and adipocytes. ω − 3 fatty acids (FAs) are also able to induce an anti-inflammatory response
through GPR120 and possibly PPARs. IL-10 is one of the well-characterized anti-inflammatory cytokines produced by these macrophages. In obesity, stressed adipocytes produce inflammatory
mediators (e.g. MCP-1, TNFα and saturated fatty acids) to induce M1 activation through inflammatory transcription factors, such as NF-κB. Macrophages respond by up-regulating inflammatory
cytokines, which activate JNK and inhibit insulin signalling pathways in the adipocyte.
Macrophages and metabolic pathologies
Macrophage infiltration and adipose tissue insulin resistance
The SVF (stromal vascular fraction) of WAT has been
studied extensively in the progression of obesity-induced insulin
resistance. Adipose tissues from lean animals and humans contain
a resident macrophage population exhibiting the M2 phenotype
[49] (Figure 3). In contrast, the obese state is characterized by
infiltration of M1 macrophages that accumulate around apoptotic
fat cells (referred to as crown-like structures) and express the
CD11c marker [49]. It has been suggested that macrophages
are recruited in response to adipocyte hypertrophy or to signals
from dying adipocytes in an attempt to restore homoeostasis
[50–52]. There they can be activated further by non-esterified
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P. Bhargava and C.-H. Lee
fatty acids released by dysfunctional fat cells (discussed below),
thus amplifying the inflammatory response. These macrophages
contain lipid droplets derived from direct lipid intake or ingestion
of dead fat cells and account for up to 40 % of the SVF in
severe cases of obesity [22]. They secrete pro-inflammatory
factors, such as MCP-1, TNFα and IL-6, which both amplify
inflammatory responses and inhibit adipocyte insulin signalling
[17,18]. Similarly, monocytes from Type 2 diabetic patients or
obese individuals express more M1 markers [40]. Conditional
depletion of CD11c-expressing macrophages or inhibition of
macrophage recruitment (e.g. MCP-1 knockout) in obese mice
resulted in a significant reduction in systemic inflammation and
an improvement in insulin sensitivity [23,24,53]. It should also
be noted that adipocytes also produce inflammatory mediators.
Because of similarities between adipocytes and macrophages,
the source of the pro-inflammatory cytokines/chemokines within
WAT is obscured. In contrast with WAT, macrophage infiltration
into BAT (brown adipose tissue) seems to be limited and, as such,
the role of macrophages in BAT is unclear [54,55].
Vascular inflammation and atherosclerosis
The most well-characterized macrophage population in the
metabolic syndrome is that of macrophages recruited to sites of
endothelial dysfunction in atherosclerosis [56,57]. Elevated LDL
(low-density lipoprotein)/cholesterol levels result in accumulation
of LDL particles in the subendothelial matrix. Careful analyses
of temporal changes leading to lesion formation revealed that
this lipid deposition is the crucial initiating event in macrophage
recruitment [57]; the accumulated LDL becomes oxidized
(oxLDL) and locally produced cytokines and chemokines, in
response to oxLDL, recruit monocytes/macrophages into the
subendothelial space. Lipid particles are taken up by macrophages
through specialized receptors SR-A (scavenger receptor A) and
CD36, among other mechanisms [58]. These processes evoke a
characteristic inflammatory response by releasing inflammatory
molecules, such as MCP-1, to the ECM (extracellular matrix),
which recruit more macrophages. The lipid-laden macrophages
become foam cells and undergo necrotic cell death releasing
intracellular components leading to a vicious cycle of chronic
inflammation [36]. Subsequently, smooth muscle cells migrate to
the lesion in response to inflammatory mediators and contribute
to fibrotic plaque formation and rupture [57].
Hepatosteatosis
Liver insulin resistance and hepatic steatosis, referred to
as NAFLDs (non-alcoholic fatty liver diseases), are major
components of the metabolic syndrome. Lipidomic analyses of
liver tissue during various stages of NAFLD show a strong
correlation between abnormal fat composition and disease
pathogenesis [59], with excess fat accumulation leading to the
recruitment of inflammatory cells [60]. Together with Kupffer
cells, these immune cells are responsible for the development
of hepatic inflammation in both humans and various animal
models. Studies have shown that depletion of Kupffer cells
or inhibition of pro-inflammatory mediators protect against the
development of NAFLD [61–63]. During high-fat-diet treatment,
depletion of Kupffer cells by GdCl3 or clodronate-encapsulated
liposomes has been shown to improve insulin sensitivity and
glucose tolerance [64–66]. A single dose of GdCl3 in mice on
normal chow enhances insulin signalling and reduces glucose
production in the liver [65]. In contrast, macrophage-specific
Ppard − / − (peroxisome-proliferator-activated receptor δ) mice,
whose macrophages/Kupffer cells exhibit a predominantly M1
phenotype, develop insulin resistance and hepatic steatosis [67].
c The Authors Journal compilation c 2012 Biochemical Society
Muscle dysfunction
The resident macrophage population in muscle has not been
characterized. Macrophages do, however, play a significant role
in muscle repair during exercise and tissue damage [68]. Studies
have shown that macrophages infiltrate fat depots formed around
the muscle in obesity [17]. Additionally, muscle can be affected
by inflammatory cytokines from other tissues, such as liver and
adipose tissue, even though it may not be a site of significant
production of inflammatory mediators [69].
INFLAMMATORY SIGNALLING AND METABOLIC DISEASES
Although the role of inflammation in atherogenesis is well
documented [36,56,57], the underlying mechanisms through
which pro-inflammatory signalling pathways cause insulin
resistance are still under investigation. One of the better-defined
mechanisms is through JNK (c-Jun N-terminal kinase) activation,
which phosphorylates IRS-1 (insulin receptor substrate-1) to
block insulin signal transduction [7,70]. Similarly, our knowledge
regarding how anti-inflammatory pathways improve metabolic
homoeostasis is limited, apart from their ability to antagonize
M1 activation [71]. In this section, we summarize various
signalling pathways mediating macrophage activation during the
pathogenesis of the metabolic syndrome.
Pro-inflammatory signalling
JNK and pro-inflammatory cytokines
JNK is an important regulatory node for inflammatory mediators,
including pro-inflammatory cytokines, TLRs (Toll-like receptors)
and ER (endoplasmic reticulum) stress (Figure 2). In obesityinduced insulin resistance and hepatic steatosis, deletion of
JNK1 in the haemopoietic compartment by bone marrow
transplantation is beneficial [72]. TNFα was one of the first
pro-inflammatory cytokines to be linked to JNK activation
[4,70]. TNFα-receptor-knockout mice show improved metabolic
homoeostasis and insulin sensitivity fed on both normal chow
and a high-fat diet [73]. Additionally, Tnf + / + bone marrow
donated to a Tnf − / − mouse induces insulin resistance in an
otherwise insulin-sensitive mouse [74]. Recently, PKR (doublestranded RNA-dependent protein kinase), which senses viral
infection, was shown to interact with JNK and IRS-1 [75].
Interestingly, PKR is able to phosphorylate IRS-1 directly,
suggesting that JNK integrates different inflammatory signals
through a multicomponent inflammatory complex.
TLRs and NF-κB
TLRs are pattern-recognition receptors that respond to pathogenic
antigens and propagate inflammatory signalling [76]. In vitro,
non-esterified fatty acids (saturated fatty acids, e.g. palmitic acid)
or ceramides can signal through TLR2 and TLR4 on macrophages
and induce pro-inflammatory gene expression [77–79]. In vivo,
whole-body TLR4 deletion improves insulin sensitivity in a lipidinfusion model of transient insulin resistance. Similarly, TLR4
loss-of-function mutation or TLR2 deficiency protects against
diet-induced obesity and insulin resistance [80–82]. However,
TLR2 and TLR4 are expressed on most tissue types including
adipocytes and hepatocytes, in addition to immune cells. The
contribution of macrophage TLR4 was examined through haemopoietic cell-specific TLR4 deletion, which ameliorates high-fatdiet-induced hepatic and adipose tissue insulin resistance [83].
Role and function of macrophages in the metabolic syndrome
TLR4 ligation promotes IKK (inhibitor of NF-κB kinase)
activation, followed by phosphorylation and nuclear translocation
of NF-κB to activate inflammatory gene transcription. Systemic
deletions of NF-κB or various IKK isoforms (e.g. IKKβ and
IKKε) prevent obesity-induced insulin resistance [36,84,85].
Myeloid-specific IKKβ deletion also leads to improved systemic
insulin sensitivity, increased glucose disposal and suppressed
hepatic glucose production [84]. In line with these observations,
salicylate treatment, known to attenuate NF-κB activation,
increases insulin sensitivity in humans [86–88].
In the setting of atherosclerosis, many studies have
demonstrated that a complete deletion of various TLR family
members reduces the lesion size in Ldlr − / − (low-densitylipoprotein receptor) or Apoe − / − (apolipoprotein E) mice [89,90].
Ldlr − / − mice transplanted with Tlr2 − / − bone marrow are
protected from atherosclerosis [89]. Similarly, Ldlr − / − mice
deficient in myeloid-specific NF-κB subunit p50 have decreased
atherosclerotic lesions [91]. Lesions in these animals exhibit near
complete loss of foam cells, supporting previous findings that
NF-κB regulates genes involved in lipid uptake and foam cell
formation [92].
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has been shown that the ER stress in the macrophage is caused
by increased aP2 (adipocyte protein 2) lipid chaperone activity,
which promotes atherogenesis [109].
Hypoxia
Activation of macrophages to a pro-inflammatory state increases
glucose influx for glycolysis, which is controlled by HIF
(hypoxia-inducible factor)-1α [110–113]. Loss of HIF-1α in
the macrophage leads to decreased pro-inflammatory cytokine
production, whereas deletion of VHL (von Hippel–Lindau
tumour-suppressor protein), a repressor of HIF-1α, results in
chronic activation of HIF-1α and uncontrolled inflammation
[112,114]. In the context of metabolic dysregulation, adipose
tissues in obese mice are hypoxic, which may cause macrophage
HIF-1α activation [51,52,115,116]. Systemic hypoxia has been
shown to induce insulin resistance and NAFLD [51,117,118].
Furthermore, high levels of hypoxia during adipose expansion
may lead to necrotic death of both adipocytes and macrophages,
since HIF-1α activation blocks physiological apoptotic cell death
[52,116,119]. Similarly, hypoxia promotes macrophage necrosis
in mouse models of atherosclerosis [119–121].
Inflammasome
The NLRP3 [NLR (nucleotide-binding-domain- and leucinerich-repeat-containing) family, pyrin-domain-containing 3]
inflammasome senses endogenous danger signals and generates
the mature secreted forms of IL-1β and IL-18 through caspase 1
activation [93–96]. In vitro, palmitic acid and ceramide are able to
induce IL-1β and caspase 1 processing in the macrophage [97].
Mice deficient in NLRP3 or ASC (apoptosis-associated specklike protein containing a caspase-recruitment domain, an adaptor
protein of the NLRP3 inflammasome) exhibit increased insulin
sensitivity in liver, WAT and muscle [97–99]. In addition, caspase
1 and IL-1β have been shown to mediate inflammasome-induced
insulin resistance [98]. Along these lines, lack of IL-1R, the
receptor for IL-1β, confers protection against insulin resistance
induced by a high-fat diet [100]. Inflammasome activation can
also be detected in atherosclerotic lesions [101,102]. Cultured
macrophages exposed to crystalline cholesterol secrete IL-1β and
IL-18 [101,102]. In concert, Ldlr − / − mice transplanted with bone
marrow from mice lacking NLRP3 or ASC show a reduction in
the lesion area and IL-18 levels [101].
Anti-inflammatory signalling
Th2 cytokines
The other end of the macrophage activity spectrum is Th2
cytokine-induced alternative activation, characterized by the
expression of M2 markers, such as Arg1, Mgl1 and YM1 [29,71].
These macrophages function to repair damage elicited by
pro-inflammatory M1 macrophages. As discussed above, in the
lean state, ATMs display an M2 phenotype, suggesting that, at
the physiological level, M2 macrophages may play an important
role in metabolic homoeostasis [49]. In line with this notion, Th2
cytokines, notably IL-13, have been detected in WAT and liver
[122]. Treatment of diet-induced obese mice with IL-4 significantly improves glucose homoeostasis and insulin sensitivity,
whereas deletion of STAT6 (signal transducer and activator of
transcription 6), a Th2 effector, worsens insulin resistance [123].
In addition, mice infected with helminth worms, which induce
an M2 response, exhibit improved insulin sensitivity [124].
Nuclear receptors
ER stress
The ER is the site of protein folding, vesicle transport and
lipid synthesis. When the capacity of ER is overburdened,
the UPR (unfolded protein response) is activated characterized
by increased activities of PERK (PKR-like ER kinase),
IRE1 (inositol-requiring enzyme 1) and ATF6 (activating
transcription factor 6) [103]. Activation of the UPR
through these signalling molecules leads to downstream
CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous
protein] activation and subsequent induction of apoptosis. The
initiation and propagation of the UPR and ER stress by obesity
and metabolic stress have been reviewed in detail [103]. ER
stress in adipose tissue or liver leads to insulin resistance, which
is associated with activation of JNK and IKK, suggesting that
ER stress is linked to inflammatory pathways [103–105]. In
atherosclerosis, chronic activation of the ER stress pathway
contributes to macrophage death and subsequent plaque necrosis
[42]. CHOP expression and macrophage apoptosis have been
correlated with advanced lesions [106,107], and deletion of CHOP
suppresses lesional macrophage death/necrosis [108]. Lastly, it
Nuclear receptors are ligand-activated transcription factors that
control important biological processes [125]. Several lipidsensing nuclear receptors, such as the PPARs (PPARα, PPARδ and
PPARγ , activated by dietary fatty acids) [126,127] and the LXRs
(liver X receptors) (LXRα and LXRβ, activated by cholesterol
metabolites) are drug targets to treat metabolic diseases [128,129].
In the macrophage, IL-4/IL-13-induced alternative macrophage
activation is associated with increased fatty acid β-oxidation and
oxidative metabolism [122,130], pathways regulated by PPARs
[131]. Accordingly, PPARδ and PPARγ have been shown to be
induced by Th2 cytokines and control M2 activation [122,132].
Mice with myeloid-specific deletion of PPARδ or PPARγ show
increased M1 and decreased M2 markers in WAT and liver and
develop systemic insulin resistance [122,132–135]. The M1/M2
paradigm is also relevant in Kupffer cells in the liver. Myeloid
PPARδ deletion worsens hepatic steatosis in mice fed on a highfat diet [122,135]. It has been shown that macrophages from
these mice produce factors that promote adipocyte and hepatocyte
dysfunction in vitro [122]. Earlier studies also demonstrated an
anti-inflammatory role for PPARs and LXRs, which correlates
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P. Bhargava and C.-H. Lee
well with the atheroprotective roles for these nuclear receptors
[136–138].
GPCRs (G-protein-coupled receptors)
Although saturated fatty acids are known to induce inflammatory
signalling pathways, epidemiological studies show that
Mediterranean diets high in polyunsaturated ω − 3 (n − 3) fatty
acids actually reduce the incidence of metabolic diseases [139–
142]. ω − 3 fatty acid derivatives, such as DHA (docosahexaenoic
acid), EPA (eicosapentaenoic acid) and resolvins, exhibit antiinflammatory activities [143]. DHA and EPA have been shown to
bind to the GPCR GPR120 on macrophage surfaces. GPR120
ligation inhibits the actions of TNFα and reverses insulin
resistance brought on by a high-fat diet [144]. GPR120 and PPARs
share several fatty acid ligands, suggesting potential cross-talk
between these two signalling pathways [145].
CONCLUDING REMARKS
The host immune system is essential for defending against foreign
pathogens. Macrophages rely on the rapid influx of extracellular
glucose for ATP production via anaerobic respiration [146–148].
As such, the ability of pathogen-stimulated macrophages to inhibit
glucose uptake and insulin sensitivity in other metabolically
demanding tissues is thought to be a mechanism by which immune
cells sequester energy stores for defence [149–151]. However, in
states of gluttony and energy storage, these evolutionary pathways
have become detrimental. As the metabolic syndrome is a rapidly
rising global epidemic affecting ∼ 8 % of the U.S. population
alone and over 170 million people worldwide, efforts to
identify effective therapies for treatment of associated pathologies
are paramount [ADA (American Diabetes Association), WHO
(World Health Organization)]. Exercise and healthy diets are most
effective in improving the outcome of the metabolic syndrome
[152,153]. However, lifestyle changes are often an unachievable
ideal for many patients, and therefore development of medications
is crucial. Growing evidence indicates that macrophage activation
plays a key role in metabolic dysregulation. Understanding the
contribution of macrophages to disease pathogenesis can help
in the development of immunometabolic therapeutics to treat
metabolic diseases.
As described above, macrophages have evolved to sense
dietary fats. The role of cholesterol in macrophage proinflammatory responses and atherosclerosis is well established.
Studies have demonstrated further that fatty acids have a broad
spectrum of activity on macrophage activation [77–79,144].
This is particularly relevant in obesity, in which the interaction
of adipocyte and macrophage through fatty-acid-dependent
mechanisms is critical to metabolic homoeostasis (Figure 3).
Dietary ω − 3 fatty acids and their derivatives, including EPA,
DHA and resolvins, can inhibit inflammatory responses through
GPCRs or PPARs [143,144] and, as such, represent an attractive
means for dietary intervention to reduce metabolic inflammation.
In addition to dietary fats, studies have suggested that some amino
acids, such as arginine and glutamine, promote insulin sensitivity
and insulin secretion. However, epidemiological data also suggest
that levels of branched-chain amino acids are associated with
diabetes as early as 12 years before the onset of frank insulin
resistance [154,155]. The role of amino-acid-sensing pathways in
macrophage function and metabolic inflammation is currently
unclear. In cultured macrophages, glutamine and arginine
are critical for cytokine secretion, eicosanoid production and
phagocytic uptake during macrophage activation [156]. mTOR
c The Authors Journal compilation c 2012 Biochemical Society
(mammalian target of rapamycin), a major amino-acid-sensing
molecule, is anti-inflammatory in the macrophage. However,
mTOR inhibition by rapamycin blocks MCP-1 production, despite
its pro-inflammatory phenotype [157]. Additional work is needed
to clarify the roles of amino acids in metabolic syndrome and
whether these effects are mediated, in part, through macrophage
activation.
Although it is evident that metabolic stress (e.g. fatty
acids, ceramides and oxLDL/cholesterol) induces macrophage
inflammation, the detailed mechanisms through which proinflammatory signalling pathways cause metabolic diseases,
notably in the setting of insulin resistance, remain unclear.
For example, contradictory results have challenged the role of
myeloid JNK1 in insulin resistance [158,159]. It appears that
the initiation of a chronic inflammatory cycle may be due to
loss of anti-inflammatory and/or regulatory signalling. However,
the beneficial effects associated with alternative activation also
require further investigation, as Th2 cytokines are known to
mediate allergic responses. Recent studies have implicated several
other immune cell types, such as T-lymphocytes, mast cells,
natural killer cells and eosinophils, in the modulation of insulin
sensitivity [124,160–165]. For example, T-cell-deficient Rag − / −
(recombination-activating gene) mice are more susceptible to dietinduced obesity and adoptive transfer of CD4 + Foxp3 + (forkhead
box P3) regulatory T-cells restores energy balance in these
mice [160,165,166]. These studies indicate that the interactions
between innate and adaptive immune systems also contribute to
the onset of the metabolic syndrome and implicate an autoimmune
response in the associated pathologies. What have not been
described are the temporal recruitment and activation of various
immune cells in metabolic tissues and the role of their interaction
in metabolic diseases.
Other anti-inflammatory or immunomodulatory mechanisms
may be relevant in metabolic homoeostasis. Certain miRNAs
(microRNAs) are up-regulated by TLR signalling and act through
NF-κB pathways to dampen the inflammatory response [167,168].
miRNAs have also been implicated in atherosclerotic plaque
initiation and expansion [169]. In addition, gut flora has been
shown to modulate energy-utilization efficiency and adiposity
and contribute to the onset of metabolic diseases [170,171].
Helminth infection is known to deactivate the immune response,
and mice infected with parasitic worms exhibit improved insulin
sensitivity, suggesting the potential use of helminthic antigens for
therapies. Lastly, exercise reduces blood inflammatory markers
and improves metabolic parameters. The so-called myokines
produced by muscle after physical activity may modulate
macrophage activation [172–175]. In fact, exercise-induced
improvements in the inflammatory profile were found to be
independent of weight loss [176,177]. Through understanding
these different aspects of metabolic-related immune responses,
it may be possible to design drugs to specifically target
the feedforward loop of metabolic-stress-induced inflammation
without unwanted side effects, such as immunosuppression or
allergic responses.
ACKNOWLEDGEMENT
We thank K. Stanya for valuable comments.
FUNDING
P.B. is supported by the National Institute of Diabetes and Digestive and Kidney Disease
(NIDDK) [training grant number T90DK070078]. C.H.L. is supported by the American
Diabetes Association, the American Heart Association and the National Institutes of Health
[grant number R01DK075046].
Role and function of macrophages in the metabolic syndrome
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