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Biochem. J. (2012) 442, 253262 (Printed in Great Britain) doi:10.1042/BJ20111708 253

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 knownfor their role as professional phagocytes, which also includeneutrophils and dendritic cells. Recent evidence indicates thatmacrophages are also key players in metabolic homoeostasis.Macrophages can be found in many tissues, where theyrespond to metabolic cues and produce pro- and/or anti-inflammatory mediators to modulate metabolite programmes.Certain metabolites, such as fatty acids, ceramides and cholesterolcrystals, elicit inflammatory responses through pathogen-sensing signalling pathways, implicating a maladaptation ofmacrophages and the innate immune system to elevated metabolic

stress associated with overnutrition in modern societies. Theoutcome of this maladaptation is a feedforward inflammatory

response leading to a state of unresolved inflammation and acollection of metabolic pathologies, including insulin resistance,fatty liver, atherosclerosis and dyslipidaemia. The presentreview summarizes what is known about the contributions ofmacrophages to metabolic diseases and the signalling pathwaysthat are involved in metabolic stress-induced macrophageactivation. Understanding the role of macrophages in theseprocesses will help us to develop therapies against detrimentaleffects of the metabolic syndrome.

Key words: inflammatory signalling, insulin resistance, macro-

phage activation, metabolic disease, metabolic syndrome, whiteadipose tissue inflammation.

INTRODUCTION

The innate immune system, which consists of macrophages,dendritic cells and a variety of other effector cells, has evolvedas a formidable defence against external threats to the human

host. When first described by Elie Metchnikoff in the late 1800s,macrophages were thought to primarily function as phagocytes.In the next several decades, intense effort went into understandingthe mechanisms that led to macrophage activation. It was not untilabout 100 years later that researchers first started to document the

innumerable roles that macrophages play [1]. We now know thatmacrophages are found throughout the body and are involved intissue homoeostasis, wound healing, general surveillance of hostthreats and, as was first observed, killing of foreign pathogens.

Abundant sources of food that have high energy contentand are enriched in saturated fats, coupled with a lack ofphysical activity, are responsible for the sharp increase in acollection of pathologies, such as obesity, hepatosteatosis, insulinresistance and atherosclerosis, known as the metabolic syndrome.All of these pathologies increase the chance of developingcardiovascular disease, diabetes mellitus and premature death[2]. The observation that anti-inflammatory salicylates couldimprove insulin sensitivity and glucose responsiveness gave thefirst indication that metabolic syndrome is associated with low-grade chronic inflammation [3]. This was followed by reports thatinflammatory cytokines, such as TNF (tumour necrosis factor), inhibit insulin responsiveness in adipocytes, providing a linkbetween inflammation and metabolic pathways [46]. Subsequentstudies have suggested that lipid overload triggers the immune

system, especially macrophages, to respond in a deleteriousmanner, in which a resolution state could not be achieved [7,8].Ataround the same time as these studies were occurring, researchersobserved that insulin resistance and hyperglycaemia led to dys-regulated immune responses and increased incidences of infectionin patients with the metabolic syndrome [916]. Together, it hasbecome evident that metabolic pathways are tightly intertwinedwith inflammatory signalling and immune responses.

As environmental sentries, it is not surprising that macrophagessense and regulate metabolism. This link between macrophages

and metabolic regulation was strengthened further with the dis-covery of resident macrophage populationsin metabolically activetissues, such as WAT (white adipose tissue) and liver [17,18]. Theinterplay between resident macrophages and pathologies associ-ated with the metabolic syndrome has been studied extensivelysince. In the present review, we highlight major contributionsof macrophages to the metabolic milieu and describe how thefunctions of macrophages are altered during states of metabolicdysfunction. We begin with a brief overview of the recruitmentof macrophages in various metabolic tissues and the diseasesassociated with their activation. We then discuss some proposedmechanisms for the inflammatory pathways that lead to patholo-gies, with an emphasis on insulin resistance/Type 2 diabetes.

AN ESSENTIAL ROLE FOR MACROPHAGES IN METABOLICPATHOLOGIES

Resident macrophages in different tissues adapt to theirlocal 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;

IFN, interferon ; IKK, inhibitor of nuclear factor B 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-B, nuclear factor B; NLRP3, NLR (nucleotide-binding-domain- and leucine-rich-repeat-

containing) family, pyrin-domain-containing 3; oxLDL, oxidized LDL; PKR, double-stranded RNA-dependent protein kinase; PPAR, peroxisome-proliferator-

activated receptor; STAT6, signal transducer and activator of transcription 6; SVF, stromal vascular fraction; TLR, Toll-like receptor; TNF, tumour necrosis

factor ; UPR, unfolded protein response; WAT, white adipose tissue.1

To whom correspondence should be addressed (email [email protected]).

c The Authors Journal compilation c 2012 Biochemical Society

www.biochemj.org
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254 P. Bhargava and C.-H. Lee

Figure 1 Metabolic dysregulation leads to a feedforward cycle of chronicinflammation

Activation of inflammatory pathways by metabolic stress leads to macrophage recruitmentto sites of affected tissues, such as vasculature, WAT, muscle and liver. There, they pick upexcess lipids and cell debris in an attempt to restore homoeostasis. The presence of persistentpro-inflammatory stimulants (e.g. fatty acids and cholesterol) causes macrophage dysfunction,including defective efferocytosis and unresolved inflammation, resulting in recruitment andactivation of more macrophages. In WAT, infiltrated macrophages are concentrated around thedying fat cells, known as the crown-like structure. In the vasculature, macrophages are enrichedin areas of fatty streaks. Inflammatory cytokines produced by activated macrophages induceinsulin resistance in major metabolic tissues, promote hepatosteatosis and facilitate foam celland plaque formation in the vessel wall.

morphological phenotypes. Resident populations, such as Kupffercells in the liver, resident macrophages in WAT and alveolarmacrophages in the lung, show expression profiles distinctfrom those of recruited macrophages responding to systemic

cues [1]. For example, studies have demonstrated that ATMs(adipose-tissue-resident macrophages) are functionally distinctfrom infiltrating macrophages (discussed below). In the processof understanding the aetiology of the metabolic syndrome, wehave begun to understand the general mechanisms underlyingmetabolic diseases, particularly the roles of macrophages inatherosclerosis and in adipose tissue insulin resistance. Owing toa lack of specific markers for resident and recruited macrophagesand the cross-talk between tissues in the progression ofmetabolic diseases, it is often difficult to tease apart the precisecontribution of individual macrophage populations to the onsetand development of systemic metabolic dysfunction. Nonetheless,it is clear that the interaction between macrophages and metaboliccells plays a key role in disease pathogenesis. Macrophages are

recruited by pro-inflammatory cytokines and chemokines to dealwith lipidoverload-induced tissuedysfunction and are also subjectto the detrimental effect of lipid influx. As such, metabolic stressinitiates a feedforward cycle of inflammatory responses, resultingin a state of unresolved chronic inflammation, with macrophagesas major culprits contributing to metabolic diseases (Figure 1).

Macrophage infiltration and activation

Recruitment

The production of chemokines, the factors that recruit immunecells to sites of trouble, is increased in states of metabolicdysfunction. MCP-1 (monocyte chemoattractant protein 1) [alsoknown as CCL2 (CC chemokine ligand 2)] and its receptor CCR2

(CC chemokine receptor 2) are the most studied chemokine

signalling molecules in metabolic diseases. Earlier studieshave demonstrated that MCP-1- and CCR2-knockout mice areprotected from atherosclerosis [1921]. CCR2-knockout micealso display attenuated macrophage accumulation and chronicinflammation in adipose tissue [22]. In addition, mice lackingMCP-1 or expressing a dominant-negative form of MCP-1 showimproved insulin sensitivity [23], whereas transgenic MCP-1

overexpression in adipose tissue causes insulin resistance andhepatic steatosis [23,24]. Other chemokines, such as osteopontin,angiopoietin-like protein 2 and CXCL14 (CXC chemokine ligand14) have also been shown to play a role in obesity-inducedmacrophage recruitment [2528]. These studies demonstrate thatmacrophage infiltration is an essential step for metabolic diseasepathogenesis.

Activation

Macrophages respond to many different types of foreign andhost-derived stimuli and exhibit very precise and co-ordinatedactivation states according to the signals they receive. These stateslie on a spectrum ranging from the pro-inflammatory state to theanti-inflammatory state [29] (Figure 2). Foreign pathogens or Th1cytokines [e.g. TNF, IL (interleukin)-1 and IFN (interferon)] transduce signals that activate macrophages to a pro-inflammatory phenotype, typically referred to as an M1 response,characterized by the expression of inflammatory markers, suchas TNF, IFN and iNOS (inducible nitric oxide synthase) [29].In contrast, M2 macrophages, induced by Th2 cytokines IL-4and IL-13, produce anti-inflammatory mediators, notably IL-10[29]. As discussed below, the M1/M2 paradigm also appliesto metabolic regulation, with M1 inducing and M2 preventingmetabolic diseases respectively (Figure 3). Interestingly, dietaryfatty acids are able to polarize macrophages towards M1 or M2activation states, depending on the signalling molecules withwhich they interact (Figure 2), thus providing a molecular basisfor the cross-talk between metabolic and inflammatory pathways.

Resolution/deactivation

The initial pro-inflammatory response is terminated by anti-inflammatory cytokines, such as IL-10, which is induced by bothM1 and M2 cytokines to deactivate macrophages and promoteresolution [3033]. Lack of this termination signal leads topersistent establishment of the inflammatory response [3436].Epidemiological studies have shown that polymorphisms in the

IL10 gene are associated with obesity and metabolic diseases [3739]. Furthermore, in patients with Type 2 diabetes, circulatingmonocytes express decreased levels of IL-10 [40]. IL-10 andother deactivating signalling molecules are also induced duringefferocytosis, a process by which macrophages engulf and clear

apoptotic cells in an effort to prevent necrosis and suppressinflammation [41]. This process is thought to help removeoxidized lipids and cholesterol and to activate Akt and NF-B(nuclear factor B) survival pathways [42]. Several studies haveshown that efficient efferocytosis is necessary to inhibit necroticplaqueformation anddefects in efferocytosislead to theformationof unstable lesions and an increase in systemic inflammation [4346]. Faulty efferocytosis has also been observed in diabetic mousemodels and is thought to promote inflammatory signalling [47].Oxidative stress and macrophage insulin resistance are two of thepotential mechanisms that cause defective efferocytosis [41,48].Therefore the combined effects of persistent pro-inflammatorystimulation from increased lipid influx, decreased deactivatingsignals and compromised efferocytosis lead to the unresolved

inflammation in metabolic dysregulation.



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Role and function of macrophages in the metabolic syndrome 255

Figure 2 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 metabolichomoeostasis, tissue repair, wound healing and angiogenesis. STAT6 is activated by Th2 cytokines to control the expression of PPAR and PPAR. Together, they regulate mitochondrial oxidativemetabolism and macrophage alternative activation. The 3 fatty acids DHA and EPA are known to ligate the GPCR GPR120 to promote anti-inflammatory response. These fatty acids can alsomediate PPAR activation. In contrast, saturated fatty acids (FAs), ceramides (metabolites of fatty acids) and cholesterol crystal can induce pro-inflammatory activation of the macrophage throughpathogen-sensing proteins TLR2/TLR4, which activate the JNK cascade, leading to NF-B relocation to the nucleus and induction of inflammatory cytokines and glycolytic pathways. Excess lipidshave also been shown to induce ER stress and inflammasome activation. Pro-inflammatory cytokines produced by these macrophages, including TNF and IL-1 , cause tissue damage and inhibitinsulin signalling, which contribute to the pathogenesis of metabolic diseases. I B, inhibitor of NF-B; iNOS, inducible nitric oxide synthase.

Figure 3 Cross-talk between macrophages and adipocytes plays an important role in adipose tissue homoeostasisIn the physiological state, ATMs exhibit an M2 phenotype, mediated by the Th2 cytokines IL-4 and IL-13, and downstream transcription factors STAT6 and PPAR /PPAR. Several cell types withinWAT have been reported to be the sources of Th2 cytokines, including T-lymphocytes, eosinophils and adipocytes. 3 fatty acids (FAs) are also able to induce an anti-inflammatory responsethrough GPR120 and possibly PPARs. IL-10 is one of the well-characterized anti-inflammatory cytokines produced by these macrophages. In obesity, stressed adipocytes produce inflammatorymediators (e.g. MCP-1, TNF and saturated fatty acids) to induce M1 activation through inflammatory transcription factors, such as NF-B. Macrophages respond by up-regulating inflammatorycytokines, 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 beenstudied extensively in the progression of obesity-induced insulinresistance. 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 byinfiltration of M1 macrophages that accumulate around apoptoticfat cells (referred to as crown-like structures) and express theCD11c marker [49]. It has been suggested that macrophagesare recruited in response to adipocyte hypertrophy or to signalsfrom dying adipocytes in an attempt to restore homoeostasis

[5052]. There they can be activated further by non-esterified



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fatty acids released by dysfunctional fat cells (discussed below),thus amplifying the inflammatory response. These macrophagescontain lipid droplets derived from direct lipid intake or ingestionof dead fat cells and account for up to 40% of the SVF insevere cases of obesity [22]. They secrete pro-inflammatoryfactors, such as MCP-1, TNF and IL-6, which both amplifyinflammatory responses and inhibit adipocyte insulin signalling

[17,18]. Similarly, monocytes from Type 2 diabetic patients orobese individuals express more M1 markers [40]. Conditionaldepletion of CD11c-expressing macrophages or inhibition ofmacrophage recruitment (e.g. MCP-1 knockout) in obese miceresulted in a significant reduction in systemic inflammation andan improvement in insulin sensitivity [23,24,53]. It should alsobe noted that adipocytes also produce inflammatory mediators.Because of similarities between adipocytes and macrophages,the source of the pro-inflammatory cytokines/chemokines withinWAT is obscured. In contrast with WAT, macrophage infiltrationinto 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 themetabolic syndrome is that of macrophages recruited to sites ofendothelial dysfunction in atherosclerosis [56,57]. Elevated LDL(low-density lipoprotein)/cholesterol levels result in accumulationof LDL particles in the subendothelial matrix. Careful analysesof temporal changes leading to lesion formation revealed thatthis lipid deposition is the crucial initiating event in macrophagerecruitment [57]; the accumulated LDL becomes oxidized(oxLDL) and locally produced cytokines and chemokines, inresponse to oxLDL, recruit monocytes/macrophages into thesubendothelial space.Lipid particles are taken up by macrophagesthrough specialized receptors SR-A (scavenger receptor A) andCD36, among other mechanisms [58]. These processes evoke acharacteristic inflammatory response by releasing inflammatory

molecules, such as MCP-1, to the ECM (extracellular matrix),which recruit more macrophages. The lipid-laden macrophagesbecome foam cells and undergo necrotic cell death releasingintracellular components leading to a vicious cycle of chronicinflammation [36]. Subsequently, smooth muscle cells migrate tothe lesion in response to inflammatory mediators and contributeto fibrotic plaque formation and rupture [57].

Hepatosteatosis

Liver insulin resistance and hepatic steatosis, referred toas NAFLDs (non-alcoholic fatty liver diseases), are majorcomponents of the metabolic syndrome. Lipidomic analyses ofliver tissue during various stages of NAFLD show a strongcorrelation between abnormal fat composition and disease

pathogenesis [59], with excess fat accumulation leading to therecruitment of inflammatory cells [60]. Together with Kupffercells, these immune cells are responsible for the developmentof hepatic inflammation in both humans and various animalmodels. Studies have shown that depletion of Kupffer cellsor inhibition of pro-inflammatory mediators protect against thedevelopment of NAFLD [6163]. During high-fat-diet treatment,depletion of Kupffer cells by GdCl3 or clodronate-encapsulatedliposomes has been shown to improve insulin sensitivity andglucose tolerance [6466]. A single dose of GdCl3 in mice onnormal chow enhances insulin signalling and reduces glucoseproduction in the liver [65]. In contrast, macrophage-specificPpard/ (peroxisome-proliferator-activated receptor ) mice,whose macrophages/Kupffer cells exhibit a predominantly M1

phenotype, develop insulin resistance and hepatic steatosis [67].

Muscle dysfunction

The resident macrophage population in muscle has not beencharacterized. Macrophages do, however, play a significant rolein muscle repair during exercise and tissue damage [ 68]. Studieshave shown that macrophages infiltrate fat depots formed aroundthe muscle in obesity [17]. Additionally, muscle can be affectedby inflammatory cytokines from other tissues, such as liver and

adipose tissue, even though it may not be a site of significantproduction of inflammatory mediators [69].

INFLAMMATORY SIGNALLING AND METABOLIC DISEASES

Although the role of inflammation in atherogenesis is welldocumented [36,56,57], the underlying mechanisms throughwhich pro-inflammatory signalling pathways cause insulinresistance are still under investigation. One of the better-definedmechanisms is through JNK (c-Jun N-terminal kinase) activation,which phosphorylates IRS-1 (insulin receptor substrate-1) toblock insulin signal transduction [7,70]. Similarly, our knowledgeregarding how anti-inflammatory pathways improve metabolic

homoeostasis is limited, apart from their ability to antagonizeM1 activation [71]. In this section, we summarize varioussignalling pathways mediating macrophage activation during thepathogenesis 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 obesity-induced insulin resistance and hepatic steatosis, deletion ofJNK1 in the haemopoietic compartment by bone marrowtransplantation is beneficial [72]. TNF was one of the firstpro-inflammatory cytokines to be linked to JNK activation[4,70]. TNF-receptor-knockout mice show improved metabolichomoeostasis and insulin sensitivity fed on both normal chowand a high-fat diet [73]. Additionally, Tnf+/+ bone marrowdonated to a Tnf/ mouse induces insulin resistance in anotherwise insulin-sensitive mouse [74]. Recently, PKR (double-stranded RNA-dependent protein kinase), which senses viralinfection, 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 signalsthrough a multicomponent inflammatory complex.

TLRs and NF-B

TLRs are pattern-recognition receptors that respond to pathogenicantigens 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 macrophagesand induce pro-inflammatory gene expression [7779]. In vivo,whole-body TLR4 deletion improves insulin sensitivity in a lipid-infusion model of transient insulin resistance. Similarly, TLR4loss-of-function mutation or TLR2 deficiency protects againstdiet-induced obesity and insulin resistance [8082]. However,TLR2 and TLR4 are expressed on most tissue types includingadipocytes and hepatocytes, in addition to immune cells. Thecontribution of macrophage TLR4 was examined through haemo-poietic cell-specific TLR4 deletion, which ameliorates high-fat-

diet-induced hepatic and adipose tissue insulin resistance [83].



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TLR4 ligation promotes IKK (inhibitor of NF-B kinase)activation, followed by phosphorylation and nuclear translocationof NF-B to activate inflammatory gene transcription. Systemicdeletions of NF-B or various IKK isoforms (e.g. IKK andIKK) prevent obesity-induced insulin resistance [36,84,85].Myeloid-specific IKK deletion also leads to improved systemicinsulin sensitivity, increased glucose disposal and suppressed

hepatic glucose production [84]. In line with these observations,salicylate treatment, known to attenuate NF-B activation,increases insulin sensitivity in humans [8688].

In the setting of atherosclerosis, many studies havedemonstrated that a complete deletion of various TLR familymembers reduces the lesion size in Ldlr/ (low-density-lipoprotein receptor) orApoe/ (apolipoprotein E) mice [89,90].

Ldlr/ mice transplanted with Tlr2/ bone marrow areprotected from atherosclerosis [89]. Similarly, Ldlr/ micedeficient in myeloid-specific NF-B subunit p50 have decreasedatherosclerotic lesions [91]. Lesions in these animals exhibit nearcomplete loss of foam cells, supporting previous findings thatNF-B regulates genes involved in lipid uptake and foam cellformation [92].

Inflammasome

The NLRP3 [NLR (nucleotide-binding-domain- and leucine-rich-repeat-containing) family, pyrin-domain-containing 3]inflammasome senses endogenous danger signals and generatesthe mature secreted forms of IL-1 and IL-18 through caspase 1activation [9396].In vitro, palmitic acid and ceramide are able toinduce IL-1 and caspase 1 processing in the macrophage [97].Mice deficient in NLRP3 or ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain, an adaptorprotein of the NLRP3 inflammasome) exhibit increased insulinsensitivity in liver, WAT and muscle [9799]. In addition, caspase1 and IL-1 have been shown to mediate inflammasome-inducedinsulin resistance [98]. Along these lines, lack of IL-1R, the

receptor for IL-1 , confers protection against insulin resistanceinduced by a high-fat diet [100]. Inflammasome activation canalso be detected in atherosclerotic lesions [101,102]. Culturedmacrophages exposed to crystalline cholesterol secrete IL-1 andIL-18 [101,102]. In concert, Ldlr/ mice transplanted with bonemarrow from mice lacking NLRP3 or ASC show a reduction inthe lesion area and IL-18 levels [101].

ER stress

The ER is the site of protein folding, vesicle transport andlipid synthesis. When the capacity of ER is overburdened,the UPR (unfolded protein response) is activated characterizedby increased activities of PERK (PKR-like ER kinase),

IRE1 (inositol-requiring enzyme 1) and ATF6 (activatingtranscription factor 6) [103]. Activation of the UPRthrough these signalling molecules leads to downstreamCHOP [C/EBP (CCAAT/enhancer-binding protein)-homologousprotein] activation and subsequent induction of apoptosis. Theinitiation and propagation of the UPR and ER stress by obesityand metabolic stress have been reviewed in detail [103]. ERstress in adipose tissue or liver leads to insulin resistance, whichis associated with activation of JNK and IKK, suggesting thatER stress is linked to inflammatory pathways [103105]. Inatherosclerosis, chronic activation of the ER stress pathwaycontributes to macrophage death and subsequent plaque necrosis[42]. CHOP expression and macrophage apoptosis have beencorrelated with advanced lesions [106,107], anddeletion of CHOP

suppresses lesional macrophage death/necrosis [108]. Lastly, it

has been shown that the ER stress in the macrophage is causedby 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)-1 [110113]. Loss of HIF-1 inthe macrophage leads to decreased pro-inflammatory cytokineproduction, whereas deletion of VHL (von HippelLindautumour-suppressor protein), a repressor of HIF-1, results inchronic activation of HIF-1 and uncontrolled inflammation[112,114]. In the context of metabolic dysregulation, adiposetissues in obese mice are hypoxic, which may cause macrophageHIF-1 activation [51,52,115,116]. Systemic hypoxia has beenshown to induce insulin resistance and NAFLD [51,117,118].Furthermore, high levels of hypoxia during adipose expansionmay lead to necrotic death of both adipocytes and macrophages,since HIF-1 activation blocks physiological apoptotic cell death[52,116,119]. Similarly, hypoxia promotes macrophage necrosisin mouse models of atherosclerosis [119121].

Anti-inflammatory signalling

Th2 cytokines

The other end of the macrophage activity spectrum is Th2cytokine-induced alternative activation, characterized by theexpression of M2 markers, such as Arg1, Mgl1 and YM1 [29,71].These macrophages function to repair damage elicited bypro-inflammatory M1 macrophages. As discussed above, in thelean state, ATMs display an M2 phenotype, suggesting that, atthe physiological level, M2 macrophages may play an importantrole in metabolic homoeostasis [49]. In line with this notion, Th2cytokines, notably IL-13, have been detected in WAT and liver

[122]. Treatment of diet-induced obese mice with IL-4 signif-icantly improves glucose homoeostasis and insulin sensitivity,whereas deletion of STAT6 (signal transducer and activator oftranscription 6), a Th2 effector, worsens insulin resistance [123].In addition, mice infected with helminth worms, which inducean M2 response, exhibit improved insulin sensitivity [124].

Nuclear receptors

Nuclear receptors are ligand-activated transcription factors thatcontrol important biological processes [125]. Several lipid-sensing nuclear receptors, such as the PPARs(PPAR, PPAR andPPAR, activated by dietary fatty acids) [126,127] and the LXRs(liver X receptors) (LXR and LXR , activated by cholesterol

metabolites) aredrug targets to treat metabolic diseases [128,129].In the macrophage, IL-4/IL-13-induced alternative macrophageactivation is associated with increased fatty acid -oxidation andoxidative metabolism [122,130], pathways regulated by PPARs[131]. Accordingly, PPAR and PPAR have been shown to beinduced by Th2 cytokines and control M2 activation [122,132].Mice with myeloid-specific deletion of PPAR or PPAR showincreased M1 and decreased M2 markers in WAT and liver anddevelop systemic insulin resistance [122,132135]. The M1/M2paradigm is also relevant in Kupffer cells in the liver. MyeloidPPAR deletion worsens hepatic steatosis in mice fed on a high-fat diet [122,135]. It has been shown that macrophages fromthese mice produce factors that promote adipocyte and hepatocytedysfunction in vitro [122]. Earlier studies also demonstrated an

anti-inflammatory role for PPARs and LXRs, which correlates



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well with the atheroprotective roles for these nuclear receptors[136138].

GPCRs (G-protein-coupled receptors)

Although saturated fatty acids are known to induce inflammatorysignalling pathways, epidemiological studies show that

Mediterranean diets high in polyunsaturated 3 (n 3) fattyacids actually reduce the incidence of metabolic diseases [139142]. 3 fatty acid derivatives, such as DHA (docosahexaenoicacid), EPA (eicosapentaenoic acid) and resolvins, exhibit anti-inflammatory activities [143]. DHA and EPA have been shown tobind to the GPCR GPR120 on macrophage surfaces. GPR120ligation inhibits the actions of TNF and reverses insulinresistance brought on by a high-fat diet [144]. GPR120 and PPARsshare several fatty acid ligands, suggesting potential cross-talkbetween these two signalling pathways [145].

CONCLUDING REMARKS

The host immune systemis essential for defending against foreignpathogens. Macrophages rely on the rapid influx of extracellularglucose for ATP production via anaerobic respiration [146148].As such, the ability of pathogen-stimulated macrophages to inhibitglucose uptake and insulin sensitivity in other metabolicallydemanding tissues is thought to be a mechanism by which immunecells sequester energy stores for defence [149151]. However, instates of gluttony and energy storage, these evolutionary pathwayshave become detrimental. As the metabolic syndrome is a rapidlyrising global epidemic affecting 8% of the U.S. populationalone and over 170 million people worldwide, efforts toidentify effective therapies for treatment of associated pathologiesare paramount [ADA (American Diabetes Association), WHO(World Health Organization)]. Exercise and healthy diets are mosteffective in improving the outcome of the metabolic syndrome

[152,153]. However, lifestyle changes are often an unachievableideal for many patients, and therefore development of medicationsis crucial. Growing evidence indicates that macrophage activationplays a key role in metabolic dysregulation. Understanding thecontribution of macrophages to disease pathogenesis can helpin the development of immunometabolic therapeutics to treatmetabolic diseases.

As described above, macrophages have evolved to sensedietary fats. The role of cholesterol in macrophage pro-inflammatory responses and atherosclerosis is well established.Studies have demonstrated further that fatty acids have a broadspectrum of activity on macrophage activation [7779,144].This is particularly relevant in obesity, in which the interactionof adipocyte and macrophage through fatty-acid-dependent

mechanisms is critical to metabolic homoeostasis (Figure 3).Dietary 3 fatty acids and their derivatives, including EPA,DHA and resolvins, can inhibit inflammatory responses throughGPCRs or PPARs [143,144] and, as such, represent an attractivemeans for dietary intervention to reduce metabolic inflammation.In addition to dietary fats, studies have suggested that some aminoacids, such as arginine and glutamine, promote insulin sensitivityand insulin secretion. However, epidemiological data also suggestthat levels of branched-chain amino acids are associated withdiabetes as early as 12 years before the onset of frank insulinresistance [154,155]. The role of amino-acid-sensing pathways inmacrophage function and metabolic inflammation is currentlyunclear. In cultured macrophages, glutamine and arginineare critical for cytokine secretion, eicosanoid production and

phagocytic uptake during macrophage activation [156]. mTOR

(mammalian target of rapamycin), a major amino-acid-sensingmolecule, is anti-inflammatory in the macrophage. However,mTOR inhibitionby rapamycin blocksMCP-1 production, despiteits pro-inflammatory phenotype [157]. Additional work is neededto clarify the roles of amino acids in metabolic syndrome andwhether these effects are mediated, in part, through macrophageactivation.

Although it is evident that metabolic stress (e.g. fattyacids, ceramides and oxLDL/cholesterol) induces macrophageinflammation, the detailed mechanisms through which pro-inflammatory signalling pathways cause metabolic diseases,notably in the setting of insulin resistance, remain unclear.For example, contradictory results have challenged the role ofmyeloid JNK1 in insulin resistance [158,159]. It appears thatthe initiation of a chronic inflammatory cycle may be due toloss of anti-inflammatory and/or regulatory signalling. However,the beneficial effects associated with alternative activation alsorequire further investigation, as Th2 cytokines are known tomediate allergic responses. Recent studies have implicated severalother immune cell types, such as T-lymphocytes, mast cells,natural killer cells and eosinophils, in the modulation of insulinsensitivity [124,160165]. For example, T-cell-deficient Rag/

(recombination-activating gene)mice are moresusceptible to diet-induced obesity and adoptive transfer of CD4+Foxp3+ (forkheadbox P3) regulatory T-cells restores energy balance in thesemice [160,165,166]. These studies indicate that the interactionsbetween innate and adaptive immune systems also contribute tothe onset of themetabolic syndrome and implicate an autoimmuneresponse in the associated pathologies. What have not beendescribed are the temporal recruitment and activation of variousimmune cells in metabolic tissues and the role of their interactionin metabolic diseases.

Other anti-inflammatory or immunomodulatory mechanismsmay be relevant in metabolic homoeostasis. Certain miRNAs(microRNAs) are up-regulated by TLR signalling and act throughNF-B pathwaysto dampenthe inflammatoryresponse[167,168].

miRNAs have also been implicated in atherosclerotic plaqueinitiation and expansion [169]. In addition, gut flora has beenshown to modulate energy-utilization efficiency and adiposityand 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 insulinsensitivity, suggesting the potential use of helminthic antigens fortherapies. Lastly, exercise reduces blood inflammatory markersand improves metabolic parameters. The so-called myokinesproduced by muscle after physical activity may modulatemacrophage activation [172175]. In fact, exercise-inducedimprovements in the inflammatory profile were found to beindependent of weight loss [176,177]. Through understandingthese different aspects of metabolic-related immune responses,

it may be possible to design drugs to specifically targetthe feedforward loop of metabolic-stress-induced inflammationwithout unwanted side effects, such as immunosuppression orallergic 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 AmericanDiabetes Association, the American Heart Association and the National Institutes of Health

[grant number R01DK075046].



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Received 23 September 2011/15 November 2011; accepted 16 November 2011Published on the Internet 13 February 2012, doi:10.1042/BJ20111708


role of macrphage in metabolic syndrome

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