Patologia e fisiopatologia generale - nuclear receptos in macrophages

FEBS Letters 582 (2008) 106–116 Minireview

Nuclear receptors in macrophages: A link between metabolism

and inflammation

a,* a,b

Attila Szanto , Tamás R}

oszer

a University of Debrecen, Medical and Health Science Center, Research Center for Molecular Medicine,

Life Science Building, Department of Biochemistry and Molecular Biology, Debrecen, Egyetem ter 1 H-4032, Hungary

b Apoptosis and Genomics Research Group of the Hungarian Academy of Sciences, Debrecen, Egyetem ter 1 H-4032, Hungary

Received 15 August 2007; accepted 6 November 2007

Available online 20 November 2007

Edited by Laszlo Nagy and Peter Tontonoz

lating lipoproteins, hemodynamic factors, endothelial cells,

Abstract Subclinical inflammation is a candidate etiological vascular smooth muscle cells, macrophages, T lymphocytes

factor in the pathogenesis of metabolic syndrome and in the pro- and a constellation of metabolic abnormalities including insu-

gression of atherosclerosis. A central role for activated macro- lin resistance, hypertension, dyslipidemia and central obesity

phages has been elucidated recently as important regulators of collectively referred to as metabolic syndrome [2]. Handling

the inflammatory process in atherosclerosis. Macrophage differ- of lipids by lesion macrophages is an important metabolic pro-

entiation and function can be modulated by a class of transcrip-

tion factors termed nuclear receptors. These are activated by cess in the context of hypercholesterolemia and the develop-

intermediary products of basic metabolic processes. In this ment of atherosclerotic lesions [3–5].

review the contribution of peroxisome proliferator-activated As a first step during atherogenesis a disturbance in endothel

receptors and liver X receptors to macrophage functions in function results in the accumulation of low-density lipoprotein

inflammation and lipid metabolism will be discussed in light of (LDL) in the sub-endothelial matrix. It is not clear how LDL

their roles in macrophages during atherosclerosis. gets modified but this leads to the appearance of minimally

In the past decade much effort has been made to understand oxidized/modified (mmLDL) and subsequently fully oxidized

the mechanisms how lipids are handled by macrophages and LDL (oxLDL) containing multiple oxidized lipid molecules.

how inflammation could promote the atherogenic process. Here, Modified lipoproteins activate both endothelial cells and

we also provide an overview of these two fields.

monocytes/macrophages resulting in further monocyte migra-

2007 Federation of European Biochemical Societies.

Published by Elsevier B.V. All rights reserved. tion into the sub-endothelial space in response to locally

produced chemoattractant molecules and cytokines like inter-

Keywords: Nuclear receptor; Inflammation; PPAR-c; LXR; feron (IFN-c), interleukin-1b (IL-1-b), IL-6, tumor necrosis

c

Atherosclerosis factor (TNF-a) [6]. Macrophages are the first cellular com-

a

ponents in lesion formation, they take up lipid particles

through special cell surface proteins, scavanger receptors

(SRs), as SR-A and CD36 that are not subjected to downreg-

ulation via a feed-back mechanism like LDL receptor. These

1. Introduction processes evoke a characteristic inflammatory response by

releasing inflammatory molecules to the extracellular environ-

Disturbances in the basic metabolism lead to several disease ment such as monocyte chemoattractant protein-1 (MCP-1),

states in western societies. Altered lipid turnover in the body which attract additional macrophages and other cells to the le-

results in pathological abnormalities. Among these, cardiovas- sion [7,8].

cular disease is the leading cause of death therefore under- Macrophages accumulate lipids from oxLDL leading to

standing the progression of atherosclerosis has placed lipid lipid-loaded foam cell formation, the characteristic cells of

metabolism and inflammation in the limelight. the early, cellular phase of lesions (Fig. 1B). Foam cells can

Atherosclerosis is a degenerative disease of the tunica intima also eliminate lipids from the sub-endothelial space through

within arteries characterized by lipid accumulation in the wall ATP-binding cassette transporters such as ABCA1, ABCG1

initially observed by the development of fatty streaks within towards high-density lipoprotein (HDL) but if the transport

the subintimal tissues [1]. Development of fatty streaks is con- is inhibited they accumulate lipids continuously resulting in in-

sidered to be driven by a pathogenic interaction between circu- creased cell death of inflammatory cells and the release of

intracellular molecules that lead to a sustained chronic inflam-

mation [4,9,10]. This chronic inflammation with secreted medi-

* Corresponding author. Fax: +36 52 314989. ators and growth factors make smooth muscle cells migrate

E-mail addresses: szantoa@dote.hu (A. Szanto), roszer@dote.hu

(T. R}

oszer). from the tunica media, proliferate and rearrange extracellular

matrix (Fig. 1B,C). This results in the formation of the late,

Abbreviations: PPAR-c, peroxisome proliferator-activated receptor c; fibrous atherosclerotic plaques. This late lesion is characterized

LXR, liver X receptor; DC, dendritic cell; IFN, interferon; IL, by calcification (sclerosis), which makes artery wall rigid and

interleukin; LDL, low density lipoprotein; LDLR, LDL receptor; SR, fragile. Finally, the originally stable lesion may change into

scavenger receptor

0014-5793/$32.00 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.febslet.2007.11.020

A. Szanto, T. R}

oszer / FEBS Letters 582 (2008) 106–116 107

There is growing appreciation that a special group of ligand-

activated transcription factors play key roles in both the met-

abolic as well as the inflammatory processes.

2. Lipid metabolism of lesion macrophages: the pros and cons for

c

peroxisome proliferator-activated receptor (PPAR-c) in

atherogenesis

Nuclear receptors are ligand-activated transcription factors.

Small lipid-soluble molecules activate them. Members of this

family can be located in the cytosol like classic steroid recep-

tors (e.g. glucocorticoid receptor) or in the nucleus binding

to the response elements of their target genes. Upon ligand

binding receptors induce transcription of their target genes.

Here, we are focusing on PPAR-c and liver X receptor

(LXR) since they have been shown to play a substantial role

in lesion macrophages during atherosclerosis. Both of them

form heterodimer with a common partner, retinoid X receptor

(RXR).

PPAR-c is most prominently expressed in adipose tissue and

myelomonocytic cells, as macrophages and dendritic cells

(DCs). PPAR-c promotes uptake of oxLDL and subsequent

differentiation of the macrophages to foam cells [11]. It is well

known, that PPAR-c is expressed in foam cells of atheroscle-

rotic lesion [11,12]. Oxidized but not native LDL promotes

its own uptake via scavenger receptor CD36 by PPAR-c [11].

Two components from oxLDL, 9-hydroxy octadecadienoic

acid (9-HODE) and 13-HODE were identified as endogenous

activators and bona fide ligands for PPAR-c [13]. There are

also other scavenger receptors involved in LDL/oxLDL up-

take, which will be discussed later. Thus, the consequence of

oxLDL internalization is the activation of PPAR-c that en-

hances further expression of CD36.

Fig. 1. The normal and pathological histology of the aortic arch. In To provide genetic evidence that PPAR-c is required for

mammals, as in mice (A) and humans (B and C) the aorta and the large macrophage development and CD36 expression PPAR-c-defi-

arteries are built up from three tissue layers, the tunica intima (TI) cient embryonic stem (ES) cells were generated. Surprisingly,

covering the luminal surface (lu) of the vessels, the tunica media (TM)

containing elastic layers and the tunica adventitia (TA). Human large these can be differentiated into macrophages in vitro. In chime-

arteries often have a subendothelial layer, which grows with age or ric mice generated with mutant ES cells PPAR-c-deficient cells

atherosclerosis. Both connective tissue and smooth muscle cells are are also able to contribute to the macrophage lineage in vivo

present in the intima. The border of the intima is delineated by the [14]. However, retroviral transfer of the receptor facilitates

internal elastic membrane, which may not be conspicuous because of

the abundance of elastic material in the tunica media (see inset in B). induction of CD36 and oxLDL uptake in response to

The tunica adventitia is a relatively thin connective tissue layer. In PPAR-c-specific agonists. There is no change in the mRNA

mice, mediastinal brown adipose cells (mf) can be involved in the level of CD36 when PPAR-c-deficient macrophages are treated

formation of the tunica adventitia. Fibroblasts are the predominant with synthetic agonists such as thiazolidinediones (TZDs).

cell type and many macrophages are also present. In mice, atheroscle- These suggest that PPAR-c is not necessary for macrophage

rotic plaques naturally cannot evolve, but in human lipid (lp)

accumulation in the so-called fatty streaks of the subendothelial layer development but required for the induction of CD36 and

can occur with aging (B). In parallel with the accumulation of modified oxLDL uptake.

LDL, macrophages invade the tunica intima and differentiate into The model above would suggest that PPAR-c is a pro-ath-

foam cells (fc). The vascular smooth muscle cells start to proliferate erogenic factor. To define the in vivo role of PPAR-c in ath-

and form a hyalinized fibrous layer (hf) in the luminal surface of the

subendothelial layer. The normal structure of elastic lamellae can be erogenesis PPAR-c null bone marrow was transplanted into

also degenerated. At the late phase of atheroprogression the subintimal LDL receptor (LDLR) knockout mice, a murine model of ath-

layer is highly infiltrated by foam cells and the extracellular matrix erosclerosis. Although animals received cholesterol-rich diet

proteins are degraded and show an eosinophilic hyalinic appearance for 8 weeks, plasma total cholesterol levels were similar in con-

(fibrous cap). Remnants of the apoptotic foam cells form a cholesterol trol and PPAR-c null bone marrow transplanted mice, how-

(chol) rich necrotic core. Sections A, B, C are stained with hematox-

ylin–chromotrope, the inset is stained with orcein. Magnifications: ever the degree of atherosclerosis was significantly increased

1000· (A), 250· (B and C), 400· (insert). in PPAR-c-deficient bone marrow transplanted recipients [15].

TZDs were also reported to inhibit the development of ath-

erosclerosis in LDLR-deficient male mice [16]. Chen and col-

an unstable vulnerable plaque due to an imbalance between leagues showed similar results in ApoE null mice, another

factors producing and degrading extracellular elements and murine model of atherosclerosis [17]. Targeted disruption of

this can easily rupture the covering endothelium leading to the PPAR-c gene in macrophages resulted in reduced total

the formation of thrombus and intravascular coagulation.

108 A. Szanto, T. R}

oszer / FEBS Letters 582 (2008) 106–116

enzyme leads to a human disease cerebrotendinous xanthoma-

plasma and HDL cholesterol levels and cholesterol efflux was tosis (CTX), a rare sterol-storage disease characterized by xan-

significantly decreased from macrophages elicited by thiogly- thomas in tendons and also in the central nervous system

colate in mutant mice [18,19]. leading to ataxia, spinal cord paresis, neurological dysfunc-

To summarize, these observations suggest that PPAR-c in tions, normolipidemic xanthomatosis and accelerated athero-

macrophages is rather anti-atherogenic, it induces cholesterol sclerosis [47–49]. We found that retinoid receptors and

removal and its synthetic agonists also exert anti-atherogenic PPAR-c induce the expression of CYP27 resulting in increased

effects. production 27-hydroxycholesterol in macrophages which acti-

vates LXR and enhances cholesterol efflux from macrophages

3. Coupling of the signaling events of PPAR-c and LXR: role for through ABC transporters [50].

endogenous ligands Thus, it seems that oxLDL uptake leads to the activation of

PPAR-c in macrophages, which in turn enhances cholesterol

As detailed above, PPAR-c enhances uptake of its own efflux via the induction of LXR and CYP27.

ligand via oxLDL but it can also induce cholesterol efflux from

macrophages via several mechanisms. An important one is the

induction of another nuclear receptor, LXR-a [15], which in 4. Alternative mechanisms for PPAR-driven lipid transport in

turn activates expression of a set of genes involved in choles- macrophages

terol efflux and transport. Two LXR proteins (a and are

b) Besides the PPAR-c-induced LXR activation there are fur-

known to exist in mammals. LXR-a is highly expressed in ther possible mechanisms that could modulate nuclear recep-

the liver but significant levels are present in macrophages, kid- tor-regulated lipid transport in macrophages.

ney, intestine, spleen and adrenal glands. LXR-b is more ubiq- Another mechanism of transcriptional regulation exists at

uitously expressed and it has been found in nearly every tissue the promoter level of target genes. Activity of the nuclear

examined [20]. Several oxysterols have been identified as receptors depends on the recruitment and exchange of co-

endogenous ligands for LXR. repressors and co-activators. Recently, a co-factor, adipocyte

LXRs have been implicated in the regulation of cholesterol enhancer-binding protein 1 (AEBP1) was shown to act as a

metabolism and clearance [21,22] and recently in inflammation transcriptional repressor that impedes macrophage cholesterol

[23,24]. Mice lacking LXR-a lose their ability to respond nor- efflux, promotes foam cell formation via PPAR-c and LXR-a

mally to dietary cholesterol and are unable to tolerate any down-regulation. Contrary to AEBP1-deficiency, AEBP1

amount of cholesterol in excess of that they synthesize de novo overexpression in macrophages is accompanied by decreased

[25–27]. These mice develop severe atherosclerosis. Serum and expression of PPAR-c, LXR-a and their target genes with con-

hepatic cholesterol levels and lipoprotein profiles of choles- comitant elevation of pro-inflammatory cytokines [51].

terol-fed animals showed no significant differences between It was also reported that activation of PPAR-c reduced

LXR-b / and wild-type mice. LXR-b / mice – in contrast cholesterol esterification, induced expression of ABCG1 and

to LXR-a / mice – maintain their resistance to dietary cho- stimulated HDL-dependent cholesterol efflux in an LXR-inde-

lesterol. Synthetic LXR agonist was shown to reduce athero- pendent manner [52] suggesting that PPAR-c can both directly

sclerosis in two mouse models, in ApoE / and in LDL and indirectly (through LXR) induce transcription of ABCG1.

receptor / mice [28].

Among LXR target genes there are lipid transporters, such

as ABCA1 and ABCG1, members of the ATP-binding cassette 5. Summary of the roles of PPARs and LXR in lipid metabolism

family of transporter proteins that are likely to be responsible of the macrophages

for cholesterol efflux [29]. They are highly expressed in lipid-

loaded macrophages [29]. Cholesterol clearance is impaired According to the current model, oxLDL activates transcrip-

in fibroblasts isolated from patients with Tangier-disease, a tion on multiple levels. It transports ligand for PPAR-c and

disease characterized by mutations in ABCA1 gene and ligand precursor for LXR. These lipid molecules turn on a spe-

marked cholesterol accumulation in macrophages and other cific transcription program within the macrophages resulting

reticuloendothelial cells [30–32] which suggests that ABCA1 in further synthesis of PPAR-c and induction of its target

has a pivotal role in cholesterol efflux. Several studies reported genes: scavenger receptors, metabolic enzymes, LXR. Conse-

that LXRs mediate cholesterol efflux by inducing cholesterol quently, further oxLDL is taken up and reverse cholesterol

transporters ABCA1, ABCG1 and later ABCG5 and ABCG8 transport is also activated through the LXR. Furthermore,

[21,29,33–35]. the survival of macrophages is also influenced by LXR. The

It is also known that oxLDL has cytotoxic effects on macro- existence of such transcriptional cascade predicts that modula-

phages [36]. Induction of apoptosis inhibitor of macrophages tion of one of the elements will affect all the others and the net

(AIM) by LXR in mouse supports macrophage survival in effect on cellular cholesterol level depends on the balance

the lesion, which allows macrophages to harbor large amount between the influx and efflux. In the context of macrophages,

of cholesterol [37–39]. an alteration in the balance between the two processes and

These observations highlight the importance of LXR activa- the subsequent overloading of macrophages with lipids results

tion in foam cells. A number of oxysterols were identified as in foam cell formation. Mutation of PPAR-c, CD36 or other

potential endogenous ligands for LXR [22,25,40–42]. One of scavenger receptors, LXR, ABC-transporters result in in-

these, 27-hydroxycholesterol is produced by a p450 enzyme creased atherosclerosis in both men and mice. However, there

CYP27, which is a mitochondrial enzyme involved in alterna- are species-specific differences: Cholesterol metabolism of the

tive bile acid synthesis [43,44] and was reported to be associ- men and mice are different: the main lipoprotein is the HDL

ated with atherosclerotic lesions [45,46]. Mutation of the

A. Szanto, T. R}

oszer / FEBS Letters 582 (2008) 106–116 109

reported demonstrating that ligand-induced SUMOylation of

in mice resulting in a protection against atherosclerosis. The PPAR-c targets the receptor to a co-repressor complex on

regulation of lipid influx and efflux by nuclear receptors is also inflammatory gene promoters [65].

different. CYP27 can be induced by retinoids and PPAR-c A reciprocal regulation was shown to exist between inflam-

only in human macrophages [50]. Deletion of CYP27 does mation and LXR-mediated lipid metabolism. LXR activators

not induce atherosclerosis in mice [53–55] only in men inhibit the expression of inflammatory mediators [23] and

[45,46]. LXR can induce its own transcription only in human microbial compounds block the induction of LXR target genes

cells [26,56,57]. AIM is regulated by LXR only in mice [37]. [24]. This