Patologia e fisiopatologia generale - nuclear receptos in macrophages

Haccumulation by releasing inflammatory molecules to the environment polarized cells) are the dominant cell types in atheromas inlike MCP-1, which attract additional macrophages and other cell typesto the lesion. This process is accompanied with the induction of contrast to T 2 cells that produce predominantly anti-inflam-Hvascular cell adhesion molecules (VCAM) on endothelial cells, which matory cytokines [9]. The dominant cytokines are IFNc,facilitates the adhesion of monocytes. IL-12, IL-15, IL-18 and TNF-a [111]. Deficiency of IFNcsignaling (IFNc receptor knockout) reduces [112] while admin-Almost every factor affecting macrophage development or istration of IFNc enhances atherogenesis in ApoE null micemigration seems to affect atherogenesis and based on in vivo [113]. Deletion of IFNc in LDLR null animals resulted in find-studies most of them function as an atherogenic factor. On ings consistent with this scenario [114]. Inhibition of T 1 sig-Hone hand PPAR-c enhances

1. macrophage/foam cell development: signaling with pentoxyphilline reduced lesion size [115].
2. IL-18: deficient animals developed reduced atherosclerosis in ApoE knockout [116].
3. IL-12: reported as a pro-atherogenic cytokine [117-121]. Blockade of IL-12 signaling by vaccination attenuates atherosclerosis [122]. IL-12 also induces T-cell recruitment to the plaque [123].
4. Uptake of modified LDL by pattern recognition receptors: There are special pattern recognition molecules (scavenger receptors [SR], Toll-like receptors [TLRs]) on the surface of macrophages originally involved in pathogen uptake.
5. The role of T 2 cytokines is more controversial as shown in both ApoE and LDLR knockout models [121,124]. This suggests that both T 1 and T 2 responses are involved in the pathogenesis of atherosclerosis with a predominant role for the pro-inflammatory molecules in the pathogenesis.

iswhich can also recognize and bind the altered structure of lipo- also supported by the observation that C57Black/6 miceproteins [89]. Several of these, SR-A and CD36, SR-B1 oxLDL (prone to T 1 responses) can develop atherosclerosis whilereceptor-1, collectin 2, CXCL16 [90], stabilin 1, 2 and SR-F on HBALB/c mice (prone to T 2 immune responses) are relativelyendothelial cells, are involved in the recognition of LDL or Hresistant to atherogenesis [125,126]. Targeted deletion of theoxLDL. The literature is controversial about the consequence transcription factor signal transducer and activator of tran-of deleting SR-A from mice. There are reports suggesting that scription 6 (STAT6) through which IL-4 regulates gene expres-it reduces atherosclerosis in ApoE [91,92] or LDLR null mice sion in BALB/c mice makes them susceptible to atherogenesis[93,94] although others did not detect significant effects in an- [126]. Binding of CD40 ligand to its receptor CD154 inducesother model of murine

atherosclerosis (ApoE3 Leiden) [95]. inflammatory response along with expression of pro-inflamma-CD36-deficient macrophages are more resistant to foam cell tory cytokines, MMPs, adhesion molecules and tissue factorformation as shown in ApoE knockout mice [96,97] and by while inhibition of CD40 ligation reduces plaque sizeusing CD36 blocking antibodies [98]. Moore and colleagues [127–130].showed that the lack of SR-A or CD36 results in decreased PPAR-c agonists inhibited the expression of several pro-lipid accumulation in peritoneal macrophages whilst associ- inflammatory molecules, e.g. inducible nitric oxide synthase,ated with increased lesion areas in ApoE null background gelatinase B [12,16,131], inflammatory cytokines like TNF-a,[99]. This could be explained by the fact that lipid uptake byA. Szanto, T. R}oszer / FEBS Letters 582 (2008) 106–116 111PPAR-c has been implicated in several functions of DCs.IL-1-b, IL-6 [132–134] and IL-12 [135]. IL-4 induces

Activation of the receptor change the expression of co-stimulatory molecules on DCs with reduced capacity to induce lymphocyte proliferation and inhibits migration by decreasing MCP-2, CCR7, EBI1 ligand chemokine. Activation of PPAR-c leads to reduced stimulation of DCs by TLR agonists. Furthermore, PPAR-c via induction of retinoic acid synthesis induces CD1d expression in DCs resulting in NKT cell proliferation and possibly altered lipid presentation by CD1 molecules. Absence

of PPAR-c in DCssignals against atherosclerosis shown in IL-10 deficient mice increases their immunogenicity [166]. 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 andformation [136–138]. 15d-PGJ blocking its T-cell stimulatory ability [167].can inhibit IL-10 signaling in a2 A recent study demonstrated that regulatory T-cells (Tregs)STAT3 dependent and PPAR-c-independent way [139]. reduced atherosclerosis when transferred, while depletion ofAnother anti-inflammatory cytokine, transforming growth +these CD25 cells increased pathogenesis [168,169]. Transferfactor (TGF-b) also inhibits atherosclerosis at several levels.b of Tregs into ApoE knockout mice attenuates atherosclerosisBy inducing collagen synthesis it stabilizes the plaque and pre- [170]. PPAR-c-expressing, but not PPAR-c null Tregs werevents formation of the vulnerable plaque. Patients with athero- shown to prevent colitis

suggesting a role for PPAR-c in regulating sclerosis have less active TGF-b in their sera [140]. Stimulating lating immune responses through Tregs [171].TGF-b signaling in mice reduces the formation of fatty streaks, whilst blocking it with neutralizing antibody accelerates disease progression in ApoE-deficient mice [141].PPAR-c agonists inhibit TGF-b-induced connective tissue 11. Perspectives growth factor expression via Smad3 [142] or fibronectin PPARs and LXRs are known as ligand-regulated transcription 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) [146]. Inflammatory processes at the lesion site elaborate growth factors from macrophages, whichstimulate smooth muscle cell proliferation and synthesis of extracellular matrix elements like eicosanoids, prostaglandins, leukotrienes, and oxidized cholesterol, respectively. Majority of these natural ligands are derived from the metabolism of unsaturated fatty acids and cholesterol, therefore disorders of lipid consumption and processing can influence transcriptional activity of PPAR and LXR-regulated genes. Here, we provided a synopsis of how the regulation of lipid homeostasis and inflammation is interlaced by macrophages within the artery wall during atherosclerosis. Destabilization of the fibrous cap is enhanced by secretion of matrix metalloproteinases (MMPs), which are type IV collagenases and degrade collagens of extracellular matrix in mammals. MMPs were

also shown to erogenesis. PPAR-c is an inflammatory mediator controllingbe 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 ofiting extracellular matrix remodeling in fatty streaks. It inhibits the anti-inflammatory effects assigned to PPAR-c activatorsexpression of MMP-9 secretion [154,155]. Interestingly, LXR are receptor-independent and inflammatory processes posi-can also repress MMP-9 expression [156]. These data suggest tively regulated by PPAR-c are still elusive. Much less isthat nuclear receptors regulate matrix degradation during late known about LXR in inflammation but based on our currentatherosclerosis 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

1. lymphocyte functions.
2. Although majority of PPAR- and LXR-induced cellular
3. Involvement of adaptive immune response in atherogenesis events result in anti-atherogenic processes, some effects arepredicted to be atherogenic at the early stage of atherogenesis.
4. Dendritic cells (DCs) are professional antigen-presenting Activation of PPARs and LXRs by exogenous ligands can becells derived from monocytes or other myeloid progenitors easily a ‘‘poison hath residence and medicine power’’, since itand 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 [157]. CCR7 the main chemo- sion macrophages and cells of the artery wall. Here, we shouldkine receptor regulating DC migration is expressed in the refer to a very recent report on increased risk of myocardiallesion [158]. 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 lesion. These cells are characterized by the expression of Va14Ja281-containing T-cell receptor (TCR) and recognize lipid antigens presented by CD1d molecules. Lack of CD1d in ApoE null mice decreases atherosclerosis. The main perspective of PPAR and LXR research is to elucidate the biological activities of each receptor subtype to facilitate the development of selective PPAR and LXR modulators that exhibit improved pharmaceutical benefits in therapy.

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.