Patologia e fisiopatologia generale - nuclear receptos in macrophages
A. Szanto, T. R}
oszer / FEBS Letters 582 (2008) 106–116 111
PPAR-c has been implicated in several functions of DCs.
IL-1-b, IL-6 [132–134] and IL-12 . IL-4 induces expression Activation of the receptor change the expression of co-stimula-
of PPAR-c  and according to our observations PPAR-c tory molecules on DCs with reduced capacity to induce lym-
signaling seems to be part of the anti-inﬂammatory response phocyte proliferation and inhibits migration by decreasing
by intensifying processes driven by IL-4 and mitigating IFN- MCP-2, CCR7, EBI1 ligand chemokine [161,162]. Activation
TNF-a-provoked pro-inﬂammatory reactions (Szanto
c-, of PPAR-c leads to reduced stimulation of DCs by TLR ago-
et al., unpublished data). nists . Furthermore, PPAR-c
It was shown recently, that activation of LXR inhibits secre- via induction of retinoic
tion of pro-inﬂammatory molecules like inducible nitric oxide acid synthesis induces CD1d expression in DCs resulting in
synthase, IL-6, IL-1-b, TNF-a . NKT cell proliferation and possibly altered lipid presentation
The anti-inﬂammatory cytokine IL-10 generates protective by CD1 molecules [164,165]. Absence of PPAR-c in DCs
signals against atherosclerosis shown in IL-10 deﬁcient mice increases their immunogenicity . LXR also alters DC phe-
by increased and in IL-10 transgenic mice by decreased lesion notype by decreasing IL-12, increasing IL-10 secretion and
formation [136–138]. 15d-PGJ blocking its T-cell stimulatory ability .
can inhibit IL-10 signaling in a
2 A recent study demonstrated that regulatory T-cells (Tregs)
STAT3 dependent and PPAR-c-independent way . reduced atherosclerosis when transferred, while depletion of
Another anti-inﬂammatory cytokine, transforming growth +
these CD25 cells increased pathogenesis [168,169]. Transfer
factor (TGF-b) also inhibits atherosclerosis at several levels.
b of Tregs into ApoE knockout mice attenuates atherosclerosis
By inducing collagen synthesis it stabilizes the plaque and pre- . PPAR-c-expressing, but not PPAR-c null Tregs were
vents formation of the vulnerable plaque. Patients with athero- shown to prevent colitis suggesting a role for PPAR-c in regu-
sclerosis have less active TGF-b in their sera . Stimulating lating immune responses through Tregs .
TGF-b signaling in mice reduces the formation of fatty
streaks, whilst blocking it with neutralizing antibody acceler-
ates disease progression in ApoE-deﬁcient mice .
PPAR-c agonists inhibit TGF-b-induced connective tissue 11. Perspectives
growth factor expression via Smad3  or ﬁbronectin PPARs and LXRs are known as ligand-regulated transcrip-
expression [143–145]. PPAR-c can repress TGF-b1 gene tion factors that play central regulatory roles in lipid uptake,
through induction of phosphatase and tensin homologue metabolism and eﬄux. Importantly, they are also implicated
deleted on chromosome 10 (PTEN) . in the regulation of inﬂammatory reactions. PPARs and LXRs
Inﬂammatory processes at the lesion site elaborate growth fac- are activated by fatty acids, oxLDL, arachidonic acid metabo-
tors from macrophages, which stimulate smooth muscle cell pro- lites like eicosanoids, prostaglandins, leukotriens and oxidized
liferation and synthesis of extracellular matrix elements cholesterol, respectively. Majority of these natural ligands are
resulting in the formation of the ﬁbrous cap. Narrowing of vessel derived from the metabolism of unsaturated fatty acids and
lumen and disruption of this plaque are the major sources of clin- cholesterol, therefore disorders of lipid consumption and
ical outcomes in atherosclerosis, such as angina pectoris, myo- processing can inﬂuence transcriptional activity of PPAR
cardial infarction and stroke. Destabilization of the ﬁbrous and LXR-regulated genes. Here, we provided a synopsis of
cap is enhanced by secretion of matrix metalloproteinases how the regulation of lipid homeostasis and inﬂammation is
(MMPs), which are type IV collagenases and degrade collagens interlaced by macrophages within the artery wall during ath-
of extracellular matrix in mammals. MMPs were also shown to erogenesis. PPAR-c is an inﬂammatory mediator controlling
be expressed in atherosclerotic lesion at high level [147–153]. many aspects of the inﬂammatory program with a net anti-ath-
There is evidence to suggest that PPAR-c is capable of inhib- erogenic consequence. However we have to note that some of
iting extracellular matrix remodeling in fatty streaks. It inhibits the anti-inﬂammatory eﬀects assigned to PPAR-c activators
expression of MMP-9 secretion [154,155]. Interestingly, LXR are receptor-independent and inﬂammatory processes posi-
can also repress MMP-9 expression . These data suggest tively regulated by PPAR-c are still elusive. Much less is
that nuclear receptors regulate matrix degradation during late known about LXR in inﬂammation but based on our current
atherosclerosis and also inhibit the formation of vulnerable knowledge we can assume further important ﬁndings concern-
plaque and subsequently thrombosis. ing the role of LXR in DC and lymphocyte functions.
Although majority of PPAR- and LXR-induced cellular
10. Involvement of adaptive immune response in atherogenesis events result in anti-atherogenic processes, some eﬀects are
predicted to be atherogenic at the early stage of atherogenesis.
Dendritic cells (DCs) are professional antigen-presenting Activation of PPARs and LXRs by exogenous ligands can be
cells derived from monocytes or other myeloid progenitors easily a ‘‘poison hath residence and medicine power’’, since it
and have been implicated in lesion progression. S-100 positive can result in multiple changes in gene expression proﬁle of le-
DCs are present at lesion sites . CCR7 the main chemo- sion macrophages and cells of the artery wall. Here, we should
kine receptor regulating DC migration is expressed in the refer to a very recent report on increased risk of myocardial
lesion . Recently, a speciﬁc group of T-cells, natural killer infarction and risk of death from cardiovascular causes in pa-
T-cells (NKT-cells) have been detected in the atherosclerotic tients treated with a TZD, Rosiglitazone upon a meta-analysis
lesion. These cells are characterized by the expression of of previous studies. However, as the authors claim there were
Va14Ja281-containing T-cell receptor (TCR) and rec-
a-chains limitations of this analysis and further comprehensive studies
ognize lipid antigens presented by CD1d molecules. Lack of are required .
CD1d in ApoE null mice decreases atherosclerosis [159,160]. The main perspective of PPAR and LXR research is to elu-
This suggests a novel crosstalk between lipid molecules and cidate the biological activities of each receptor subtype to facil-
the immune system at the level of DC function. itate the development of selective PPAR and LXR modulators
112 A. Szanto, T. R}
oszer / FEBS Letters 582 (2008) 106–116
that exhibit improved pharmaceutical beneﬁts in therapy of  Chen, Z. et al. (2001) Troglitazone inhibits atherosclerosis in
apolipoprotein E-knockout mice: pleiotropic eﬀects on CD36
atherosclerosis and metabolic syndrome. Also a huge challenge expression and HDL. Arterioscler. Thromb. Vasc. Biol. 21, 372–377.
for the future is the characterization of the species-speciﬁcity of  Akiyama, T.E. et al. (2002) Conditional disruption of the
the identiﬁed processes, since many reported mechanisms are peroxisome proliferator-activated receptor gamma gene in mice
seemed to be human or murine-speciﬁc. Furthermore, macro- results in lowered expression of ABCA1, ABCG1, and apoE in
macrophages and reduced cholesterol eﬄux. Mol. Cell Biol. 22,
phage biology has also been shown to be more complex than 2607–2619.
previously thought. The identiﬁcation of various monocyte  Babaev, V.R., Yancey, P.G., Ryzhov, S.V., Kon, V., Breyer,
subtypes, diﬀerently activated macrophage subsets and the M.D., Magnuson, M.A., Fazio, S. and Linton, M.F. (2005)
involvement of DCs in metabolic disorders predict that much Conditional knockout of macrophage PPARgamma increases
remained to be discovered in this ﬁeld. atherosclerosis in C57BL/6 and low-density lipoprotein receptor-
deﬁcient mice. Arterioscler. Thromb. Vasc. Biol. 25, 1647–1653.
 Willy, P.J., Umesono, K., Ong, E.S., Evans, R.M., Heyman,
Acknowledgements: The authors are grateful for L. Nagy for critical R.A. and Mangelsdorf, D.J. (1995) LXR, a nuclear receptor that
reading of the manuscript and for insightful discussions. A.Sz. is sup- deﬁnes a distinct retinoid response pathway. Genes Dev. 9,
ported by the Hungarian Academy of Sciences (Bolyai Scholarship) 1033–1045.
and by Grants from Hungarian Science Research Fund (OTKA/  Repa, J.J. et al. (2000) Regulation of absorption and ABC1-
61814) and from the University of Debrecen (Mecenatura). T.R. is also mediated eﬄux of cholesterol by RXR heterodimers. Science
supported by the Hungarian Academy of Sciences. 289, 1524–1529.
 Fu, X., Menke, J.G., Chen, Y., Zhou, G., MacNaul, K.L.,
Wright, S.D., Sparrow, C.P. and Lund, E.G. (2001) 27-
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+1 anno fa
I contenuti di questa pagina costituiscono rielaborazioni personali del Publisher valeria0186 di informazioni apprese con la frequenza delle lezioni di Patologia e Fisiopatologia Generale e studio autonomo di eventuali libri di riferimento in preparazione dell'esame finale o della tesi. Non devono intendersi come materiale ufficiale dell'università Seconda Università di Napoli SUN - Unina2 o del prof Castoria Gabriella.
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