Anti-inflammatory effects of HDL in macrophages predominate over pro-inflammatory effects in atherosclerotic plaques
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129347 | GEO | 2020/04/04
REPOSITORIES: GEO
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Project description:Anti-inflammatory effects of HDL in macrophages predominate over pro-inflammatory effects in atherosclerotic plaques
| PRJNA530992 | ENA
Project description:Elevated plasma levels of High Density Lipoprotein (HDL) are associated with decreased risk of cardiovascular disease (CVD). The protective role of HDL in atherosclerosis has been attributed primarily to its ability to remove excess cholesterol from lipid-laden macrophages (foam cells) within the arterial walls. However, clinical trials that raise HDL cholesterol levels have failed to show a benefit casting doubts on our basic understanding of HDL function. Atherosclerosis is a chronic inflammatory condition underlying CVD and driven in part by the recognition of metabolic danger signals by innate immune receptors on macrophages. A potential feature that could contribute to HDL’s protective effects in CVD could be HDL's anti-inflammatory nature, such as its ability to reduce endothelial cell activation. However, the molecular mechanisms by which HDL reduces inflammatory macrophage responses remain poorly understood and difficult to separate from its cholesterol depleting activity. Here we show that HDL protects against Toll like receptor (TLR)-induced inflammation both in vivo and in vitro under normocholesteremic conditions by suppressing the transcription of inflammatory cytokines in a manner independent of its ability to remove cellular cholesterol. We identify Activating Transcription Factor 3 (ATF3), a transcriptional repressor of the CREB family of basic leucine zipper transcription factors, as a HDL-inducible regulator of macrophage activation. HDL’s ability to down modulate TLR responses was severely compromised in ATF3-deficient cells demonstrating that ATF3 mediates HDL's anti-inflammatory effects and may explain the broad anti-inflammatory functions of HDL.
2013-12-08 | GSE44034 | GEO
Project description:Elevated plasma levels of High Density Lipoprotein (HDL) are associated with decreased risk of cardiovascular disease (CVD). The protective role of HDL in atherosclerosis has been attributed primarily to its ability to remove excess cholesterol from lipid-laden macrophages (foam cells) within the arterial walls. However, clinical trials that raise HDL cholesterol levels have failed to show a benefit casting doubts on our basic understanding of HDL function. Atherosclerosis is a chronic inflammatory condition underlying CVD and driven in part by the recognition of metabolic danger signals by innate immune receptors on macrophages. A potential feature that could contribute to HDL’s protective effects in CVD could be HDL's anti-inflammatory nature, such as its ability to reduce endothelial cell activation. However, the molecular mechanisms by which HDL reduces inflammatory macrophage responses remain poorly understood and difficult to separate from its cholesterol depleting activity. Here we show that HDL protects against Toll like receptor (TLR)-induced inflammation both in vivo and in vitro under normocholesteremic conditions by suppressing the transcription of inflammatory cytokines in a manner independent of its ability to remove cellular cholesterol. We identify Activating Transcription Factor 3 (ATF3), a transcriptional repressor of the CREB family of basic leucine zipper transcription factors, as a HDL-inducible regulator of macrophage activation. HDL’s ability to down modulate TLR responses was severely compromised in ATF3-deficient cells demonstrating that ATF3 mediates HDL's anti-inflammatory effects and may explain the broad anti-inflammatory functions of HDL. Bone marrow-derived macrophages (BMDMs) were obtained by culturing bone marrow cells from 6 to 8 week old wildtype C57BL/6 mice in DMEM supplemented with 10% FCS, 10 mg ml-1 Ciprobay-500 and 40 ng ml-1 M-CSF (R & D Systems). BMDMs of wt mice were pretreated for 6 h with HDL (2 mg ml-1 ) then stimulated with CpG (100 nM) for 4 h. Further wild type or Atf3-deficient BMDMs were pretreated with 2 mg ml-1 HDL for 6 h and subsequently stimulated with CpG (100 nM) or P3C (50 ng ml-1) for 4 h. For carotid artery injury approximately 12-week old male WT and Atf3-deficient mice were anesthetized with i.p. injection of 150 mg/kg ketaminehydrochloride (Ketanest, Pharmacia) and 0.1 mg/kg xylazinehydrochloride (Rompun 2%, Bayer). A small incision from the cranial apex of the sternum to just below the mandible was made. After careful preparation of an approximately 6 mm long segment proximal of the bifurcation, the common carotid artery was electrically denuded. A 4 mm long lesion was made by applying two serial 5 second bursts of 2 Watt using 2 mm wide forceps. The skin was then sutured and the mice allowed to recover in individual cages before returning to their littermates. Three hours later the mice received a single 200 ?l i.v. injection of 20 mg/kg HDL or PBS.
2013-12-08 | E-GEOD-44034 | biostudies-arrayexpress
Project description:Long-term high fat feeding leads to hepatic steatosis, dyslipidemia, and a pro-inflammatory state. In a previous study, we observed this dysregulated metabolic phenotype when C57BL/6 mice were fed a high fat diet (HFD) for sixteen weeks. Additionally, a five-fold increase in liver gene expression of serum amyloid A-1 (SAA-1), an acute phase response protein that associates with high density lipoprotein (HDL), was observed. Inflammation induced changes composition may alter HDL functions, including anti-oxidant, anti-inflammatory and reverse cholesterol transport properties. Diet-induced onset and progression of HDL dysfunction is poorly understood. To examine the relationship between high fat diet and HDL dysfunction, we performed a short-term diet study. Four-week high fat feeding caused an increase in total plasma cholesterol compared with mice fed normal control diet (ND). No change in plasma triglycerides or development of hepatic steatosis was observed. These mice did however show evidence for increase in acute phase reactants, with a 3.25-fold increase in SAA-1 expression in liver. Heavy water labelling was used to determine the turnover rates of proteins associated with HDL. High fat diet resulted in increased fractional catabolic rate (HFD vs ND) of several acute phase response proteins involved ininnate immunity , including – Complement C3 (7.06 ± 0.99 vs 5.20 ± 0.56 %/h, p < 0.005), complement factor B (6.17 ± 0.59 vs 5.09 ± 0.87 %/h, p < 0.05), complement Factor H (4.16 ± 0.41 vs 3.56 ± 0.36 %/h, p < 0.05), and Complement factor I (3.50 ± 0.26 vs 2.75 ± 0.14 %/h, p < 0.005). Our findings suggest that early immune response-induced inflammatory remodeling of HDL precedes the diet-induced steatosis and dyslipidemia. Early HDL dysfunction reflected on impaired reverse cholesterol transport likely results in increase in plasma cholesterol in the absence of other lipid abnormalities.
2021-09-08 | PXD010272 | Pride
Project description:Background: High density lipoprotein (HDL) protects the artery wall by removing cholesterol from lipid-laden macrophages. However, recent evidence suggests that it might also inhibit atherogenesis by combating inflammation. Methods and Results: To identify potential anti-inflammatory mechanisms, we challenged macrophages with lipopolysaccharide (LPS), an inflammatory microbial ligand for Toll-like receptor 4 (TLR4). HDL inhibited the expression of 33% (301 of 911) of the genes normally induced by LPS, microarray analysis revealed. One of its major targets was the type I interferon response pathway, a family of potent viral immunoregulators controlled by TLR4 and the TRAM/TRIF signaling pathway. Unexpectedly, HDL’s ability to inhibit gene expression was independent of cellular cholesterol stores. Moreover, it was unaffected by downregulation of two ATP-binding cassette transporters, ABCA1 and ABCG1, that promote cholesterol efflux. To examine the pathway’s potential in vivo relevance, we used mice deficient in apolipoprotein (apo) A-I, HDL’s major protein. After infection with Salmonella (a Gram-negative bacterium that expresses LPS), apoA-I–deficient mice had 6-fold higher plasma levels of interferon-beta-a key regulator of the type I interferon response than did wild-type mice. Conclusions: HDL inhibits a subset of LPS-stimulated macrophage genes that regulate the type I interferon response, and its action is independent of sterol metabolism. These findings raise the possibility that regulation of macrophage genes by HDL might link innate immunity and cardioprotection. 12 arrays, 3 experimental groups, mMncN (no treatment), mMncL (LPS treated, exposed for 4 h to serum-free medium or serum-free medium supplemented with 100 ng/mL of LPS), and mMwtL (HDL treated, Macrophages were treated for 4 h with serum-free medium or serum-free medium supplemented with 50 mg/mL of HDL, washed twice with PBS).
2010-10-01 | E-GEOD-19340 | biostudies-arrayexpress
Project description:Inhibition of miR-33 results in increased cholesterol efflux and HDL-cholesterol levels in mice. In this study we examined the effect of miR-33 inhibition in a mouse model of atherosclerosis and observed significant reduction in atherosclerotic plaque size. At the end of the study, gene expression in macrophages from the atherosclerotic plaques was assessed. The results demonstrated a reduction in inflammatory gene expression and increased levels of mRNAs containing miR-33 binding sites. LDLR-/- mice on a Western diet with established atherosclerosis were switched to normal chow and treated with anti-miR-33, control anti-miR, or saline (n=4/group) for 4 weeks. Gene expression profiling was performed on macrophages in aortic plaques isolated at the end of the treatment period by laser capture microdissection.
2011-05-20 | E-GEOD-28783 | biostudies-arrayexpress
Project description:Statins are efficient in preventing cardiovascular disease progression, but their effects in the absence of low density lipoprotein receptor (LDLR) and on the risk of diabetes are not yet well characterized. The aim was to clarify systemic and pleiotropic effects of Rosuvastatin on cardiovascular and diabetic phenotypes in hypercholesterolemic prediabetic mice. The IGF-II/LDLR-/-ApoB100/100 animals were tested for Rosuvastatin effects on plasma glucose, insulin, lipids, atherosclerosis and liver steatosis. To achieve a more comprehensive view, genes differentially expressed in response to Rosuvastatin were identified by RNA sequencing in liver tissue. Rosuvastatin significantly reduced plasma cholesterol in hypercholesterolemic LDLR – deficient mice, but had no effects on atherosclerosis development at aortic sinus level and in coronary arteries. Rosuvastatin also significantly reduced liver steatosis without any pronounced effects on glucose or insulin levels. RNA sequencing revealed that Rosuvastatin – responsive hepatic genes are involved in cholesterol metabolism and in anti-inflammatory response. In addition, significant changes were detected in the expression of Perilipin 4 and 5 which are involved in lipid droplet formation in the liver. For the first time it was shown that Tribbles proteins are affected by Rosuvastatin treatment in the hypercholesterolemic mice. In conclusion, Rosuvastatin treatment had several positive effects in hypercholesterolemic mice showing early signs of diabetes, and many of these outcomes are unrelated to direct effects on cholesterol and lipoprotein metabolism. These results increase our understanding about the systemic and pleiotropic effects of Rosuvastatin in the absence of LDLR expression.
2018-11-23 | GSE111125 | GEO
Project description:Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids
| PRJNA814644 | ENA
Project description:Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
2024-02-19 | GSE250274 | GEO
Project description:Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
2024-02-19 | GSE250273 | GEO