scholarly journals Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis

2020 ◽  
Vol 21 (23) ◽  
pp. 9329
Author(s):  
Elien Wouters ◽  
Elien Grajchen ◽  
Winde Jorissen ◽  
Tess Dierckx ◽  
Suzan Wetzels ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mononuclear Cells ◽  
Foam Cell ◽  
Cell Formation ◽  
Autoimmune Disorder ◽  
Foam Cell Formation ◽  
Peroxisome Proliferator ◽  
Peripheral Blood Mononuclear ◽  
Peroxisome Proliferator Activated Receptors ◽  
Pparγ Expression

Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it has been reported that PPARγ expression is decreased in peripheral blood mononuclear cells of MS patients. The goal of the present study was to determine to what extent PPARγ, as well as the closely related nuclear receptors PPARα and β and LXRα and β, are differentially expressed in monocytes from MS patients and how this change in expression affects the function of monocyte-derived macrophages. We demonstrate that monocytes of relapsing-remitting MS patients display a marked decrease in PPARγ expression, while the expression of PPARα and LXRα/β is not altered. Interestingly, exposure of monocyte-derived macrophages from healthy donors to MS-associated proinflammatory cytokines mimicked this reduction in PPARγ expression. While a reduced PPARγ expression did not affect the inflammatory and phagocytic properties of myelin-loaded macrophages, it did impact myelin processing by increasing the intracellular cholesterol load of myelin-phagocytosing macrophages. Collectively, our findings indicate that an inflammation-induced reduction in PPARγ expression promotes myelin-induced foam cell formation in macrophages in MS.

scholarly journals Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Véronique Ferret-Sena ◽  
Alexandra Maia e Silva ◽  
Armando Sena ◽  
Inês Cavaleiro ◽  
José Vale ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mrna Expression ◽  
Mononuclear Cells ◽  
Peroxisome Proliferator ◽  
Healthy Controls ◽  
Autoimmune Encephalomyelitis ◽  
Peripheral Blood Mononuclear ◽  
Natalizumab Treatment ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARβ/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARβ/δmRNA (p=0.009) in comparison to baseline, while mRNA expression of PPARγand CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p=0.026andp=0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p=0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy.

scholarly journals 12-Hydroxyeicosapentaenoic acid inhibits foam cell formation and ameliorates high-fat diet-induced pathology of atherosclerosis in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takahiro Nagatake ◽  
Yuki Shibata ◽  
Sakiko Morimoto ◽  
Eri Node ◽  
Kento Sawane ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Foam Cell ◽  
Linseed Oil ◽  
Cell Formation ◽  
Chronic Inflammatory Disease ◽  
Foam Cell Formation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
High Fat ◽  
The Impact

AbstractAtherosclerosis is a chronic inflammatory disease associated with macrophage aggregate and transformation into foam cells. In this study, we sought to investigate the impact of dietary intake of ω3 fatty acid on the development of atherosclerosis, and demonstrate the mechanism of action by identifying anti-inflammatory lipid metabolite. Mice were exposed to a high-fat diet (HFD) supplemented with either conventional soybean oil or α-linolenic acid-rich linseed oil. We found that as mice became obese they also showed increased pulsatility and resistive indexes in the common carotid artery. In sharp contrast, the addition of linseed oil to the HFD improved pulsatility and resistive indexes without affecting weight gain. Histological analysis revealed that dietary linseed oil inhibited foam cell formation in the aortic valve. Lipidomic analysis demonstrated a particularly marked increase in the eicosapentaenoic acid-derived metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in the serum from mice fed with linseed oil. When we gave 12-HEPE to mice with HFD, the pulsatility and resistive indexes was improved. Indeed, 12-HEPE inhibited the foamy transformation of macrophages in a peroxisome proliferator-activated receptor (PPAR)γ-dependent manner. These results demonstrate that the 12-HEPE-PPARγ axis ameliorates the pathogenesis of atherosclerosis by inhibiting foam cell formation.

scholarly journals PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPARγ Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Wen-Lin Cheng ◽  
Quan Zhang ◽  
Bo Li ◽  
Jian-Lei Cao ◽  
Lin Jiao ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Foam Cell ◽  
Macrophage Polarization ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Loss Of Function ◽  
M1 Macrophage ◽  
Pparγ Expression

Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

scholarly journals Decaffeinated coffee and green tea extract inhibit foam cell atherosclerosis by lowering inflammation and improving cholesterol influx/efflux balance through upregulation of PPARγ and miR-155

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 1175
Author(s):  
Ermin Rachmawati ◽  
Mohammad Saifur Rohman ◽  
Djanggan Sargowo ◽  
Umi Kalsum ◽  
Diana Lyrawati ◽  
...  
Keyword(s):  
Green Tea ◽  
Cholesterol Metabolism ◽  
Foam Cell ◽  
Cell Formation ◽  
Green Tea Extract ◽  
Foam Cell Formation ◽  
Cell Numbers ◽  
Decaffeinated Coffee ◽  
Tea Extract ◽  
Pparγ Expression

Background: Foam cells are markers of atherosclerosis and characterise advanced atherosclerotic plaque, stimulated by inflammation caused by high lipid levels in macrophages. The combination of decaffeinated coffee and green tea extract (DCGTE) has been suggested to have a role in foam cell inhibition. Objective: we investigated the inhibiting role of DCGTE against foam cell formation, through modulation of the inflammation process and cholesterol metabolism in macrophage colony stimulating factor- (M-CSF) and oxidized low-density lipoprotein (oxLDL)-exposed macrophages. Methods: Coffee and green tea were extracted by filtration and infusion respectively, and underwent decaffeination using active carbon and blanching methods, respectively. Cells were administered 160/160 and 320/320μg/ml of DCGTE. Foam cell formation was observed using a light microscope after staining with Oil Red O (ORO), and the accumulation of lipids in macrophages with ELISA. Observations of lipid influx and efflux were determined through semiquantitative cluster differentiation 36 (CD36) and ATP binding cassette transporter A1 (ABCA1) expression through immunofluorescence. The inflammation process was quantified using inflammatory/anti-inflammatory markers, e.g., tumor necrosis factor α (TNFα) and interleukin 10 (IL10) with ELISA. Peroxisome proliferator activated response γ (PPARγ) expression and activity were assessed with PCR and ELISA, respectively. The expression of microRNA 155 (miR-155) was examined using qPCR. Results: DCGTE at the above concentrations tended to reduce foam cell numbers, significantly inhibited lipid accumulation (p=0.000), reduced CD36 expression (p=0.000) and TNFα secretion (p=0.000) in Raw264.7 exposed to M-CSF 50ng/ml and oxLDL 50μg/ml.  PPARγ expression (p=0.00) and activity (p=0.001), miR-155 relative expression (p=0.000), and IL10 production (p=0.000) also increased. Conclusion: DCGTE lowered foam cell numbers, possibly through attenuation of the inflammatory process and improvement of lipid/efflux mechanisms in M-CSF and oxLDL-stimulated Raw264.7 cells, via upregulation of PPARγ and miR-155.  Our results suggest DCGTE may help prevent atherosclerosis-based diseases.

Induction of dendritic cell-like phenotype in macrophages during foam cell formation

2007 ◽  
Vol 29 (2) ◽  
pp. 149-160 ◽  
Author(s):  
Hyung Jun Cho ◽  
Pavel Shashkin ◽  
Christian A. Gleissner ◽  
Dane Dunson ◽  
Nitin Jain ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cell ◽  
Mononuclear Cells ◽  
Foam Cell ◽  
Expression Patterns ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Platelet Factor ◽  
Significant Differential Expression

Foam cell formation from monocyte-derived macrophages is a hallmark of atherosclerotic lesions. Aspects of this process can be recapitulated in vitro by exposing M-CSF-induced or platelet factor 4 (CXCL4)-induced macrophages to oxidized (ox) or minimally modified (mm) low density lipoprotein (LDL). We measured gene expression in peripheral blood mononuclear cells, monocytes, and macrophages treated with CXCL1 (GRO-α) or CCL2 (MCP-1), as well as foam cells induced by native LDL, mmLDL, or oxLDL using 22 Affymetrix gene chips. Using an advanced Bayesian error-pooling approach and a heterogeneous error model with a false discovery rate <0.05, we found 5,303 of 22,215 probe sets to be significantly regulated in at least one of the conditions. Among a subset of 917 candidate genes that were preselected for their known biological functions in macrophage foam-cell differentiation, we found that 290 genes met the above statistical criteria for significant differential expression patterns. While many expected genes were found to be upregulated by LDL and oxLDL, very few were induced by mmLDL. We also found induction of unexpected genes, most strikingly MHC-II and other dendritic cell markers such as CD11c. The gene expression patterns in response to oxLDL were similar in M-CSF-induced and CXCL4-induced macrophages. Our findings suggest that LDL and oxLDL, but not mmLDL, induce a dendritic cell-like phenotype in macrophages, suggesting that these cells may be able to present antigens and support an immune response.

scholarly journals Regulation of Macrophage Cholesterol Efflux through Hydroxymethylglutaryl-CoA Reductase Inhibition

2005 ◽  
Vol 280 (23) ◽  
pp. 22212-22221 ◽  
Author(s):  
Carmen A. Argmann ◽  
Jane Y. Edwards ◽  
Cynthia G. Sawyez ◽  
Caroline H. O'Neil ◽  
Robert A. Hegele ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Dominant Negative ◽  
Foam Cell Formation ◽  
Peroxisome Proliferator ◽  
Very Low Density Lipoproteins ◽  
Peroxisome Proliferator Activated Receptor ◽  
Abca1 Expression ◽  
Coa Reductase

The cholesterol biosynthetic pathway produces numerous signaling molecules. Oxysterols through liver X receptor (LXR) activation regulate cholesterol efflux, whereas the non-sterol mevalonate metabolite, geranylgeranyl pyrophosphate (GGPP), was recently demonstrated to inhibit ABCA1 expression directly, through antagonism of LXR and indirectly through enhanced RhoA geranylgeranylation. We used HMG-CoA reductase inhibitors (statins) to test the hypothesis that reduced synthesis of mevalonate metabolites would enhance cholesterol efflux and attenuate foam cell formation. Preincubation of THP-1 macrophages with atorvastatin, dose dependently (1–10 μm) stimulated cholesterol efflux to apolipoprotein AI (apoAI, 10–60%, p < 0.05) and high density lipoprotein (HDL3) (2–50%, p < 0.05), despite a significant decrease in cholesterol synthesis (2–90%). Atorvastatin also increased ABCA1 and ABCG1 mRNA abundance (30 and 35%, p < 0.05). Addition of mevalonate, GGPP or farnesyl pyrophosphate completely blocked the statin-induced increase in ABCA1 expression and apoAI-mediated cholesterol efflux. A role for RhoA was established, because two inhibitors of Rho protein activity, a geranylgeranyl transferase inhibitor and C3 exoenzyme, increased cholesterol efflux to apoAI (20–35%, p < 0.05), and macrophage expression of dominant-negative RhoA enhanced cholesterol efflux to apoAI (20%, p < 0.05). In addition, atorvastatin increased the RhoA levels in the cytosol fraction and decreased the membrane localization of RhoA. Atorvastatin treatment activated peroxisome proliferator activated receptor γ and increased LXR-mediated gene expression suggesting that atorvastatin induces cholesterol efflux through a molecular cascade involving inhibition of RhoA signaling, leading to increased peroxisome proliferator activated receptor γ activity, enhanced LXR activation, increased ABCA1 expression, and cholesterol efflux. Finally, statin treatment inhibited cholesteryl ester accumulation in macrophages challenged with atherogenic hypertriglyceridemic very low density lipoproteins indicating that statins can regulate foam cell formation.

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