Abstract 260: Apolipoprotein A-I Binding Protein Regulates Macrophage Polarization in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Dina A Schneider ◽  
Longhou Fang ◽  
Yury I Miller
Keyword(s):  
Lipid Rafts ◽  
Lipid Accumulation ◽  
Cholesterol Efflux ◽  
Binding Protein ◽  
Macrophage Polarization ◽  
Atherosclerotic Lesion ◽  
Negative Regulator ◽  
High Cholesterol Diet ◽  
Apolipoprotein A ◽  
M1 Macrophage

Our laboratory recently demonstrated that Apolipoprotein A-I Binding Protein (AIBP), an evolutionarily conserved intracellular and secreted protein, mediates cholesterol efflux from endothelial cells, which in turn disrupts lipid rafts and limits angiogenic signaling. Since lipid rafts are implicated in multiple cell signal cascades, to better understand the in vivo role of AIBP our laboratory has generated Apoa1bp -/- mice. The Apoa1bp -/- mice exhibit increased levels of inflammatory cytokines, and have an increased content of M1 macrophages in white adipose tissue in comparison to wild type mice when challenged with a high fat diet. Since AIBP accelerates cholesterol efflux from macrophages to HDL, and vascular lipid accumulation and inflammation are key factors in atherosclerosis, we hypothesized that AIBP is atheroprotective by suppressing macrophage lipid accumulation and inflammatory M1 macrophage polarization. Immunohistochemistry shows that AIBP is present in atherosclerotic lesion macrophages. However, elicited macrophages lacking AIBP expression do not exhibit any impairment in their ability to polarize to M1, suggesting that deficiency in secreted extracellular AIBP may be responsible for the M1 phenotype observed in Apoa1bp -/- mice. Indeed, treating macrophages with recombinant AIBP prior to polarization resulted in suppression of M1 polarization. In a high-cholesterol diet feeding experiment, Apoa1bp -/- Ldlr -/- mice had increased M1 macrophage content in their aorta and aortic root atherosclerotic lesions, as determined by FACS and immunohistochemistry, respectively. In conclusion, AIBP is an important negative regulator of macrophage polarization and lipid accumulation. A better understanding of AIBP’s regulatory functions in the context of atherosclerosis will provide new mechanistic insights and targeted therapies.

scholarly journals Cholesterol Efflux-Independent Modification of Lipid Rafts by AIBP (Apolipoprotein A-I Binding Protein)

2020 ◽  
Vol 40 (10) ◽  
pp. 2346-2359
Author(s):  
Hann Low ◽  
Nigora Mukhamedova ◽  
Luciano dos Santos Aggum Capettini ◽  
Yining Xia ◽  
Irena Carmichael ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Nicotinamide Adenine Dinucleotide ◽  
Metabolic Pathways ◽  
Cholesterol Efflux ◽  
Binding Protein ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Underlying Mechanism ◽  
Atp Binding Cassette Transporter ◽  
Apolipoprotein A ◽  
Phosphatidylinositol 3

Objective: AIBP (apolipoprotein A-I binding protein) is an effective and selective regulator of lipid rafts modulating many metabolic pathways originating from the rafts, including inflammation. The mechanism of action was suggested to involve stimulation by AIBP of cholesterol efflux, depleting rafts of cholesterol, which is essential for lipid raft integrity. Here we describe a different mechanism contributing to the regulation of lipid rafts by AIBP. Approach and Results: We demonstrate that modulation of rafts by AIBP may not exclusively depend on the rate of cholesterol efflux or presence of the key regulator of the efflux, ABCA1 (ATP-binding cassette transporter A-I). AIBP interacted with phosphatidylinositol 3-phosphate, which was associated with increased abundance and activation of Cdc42 and rearrangement of the actin cytoskeleton. Cytoskeleton rearrangement was accompanied with reduction of the abundance of lipid rafts, without significant changes in the lipid composition of the rafts. The interaction of AIBP with phosphatidylinositol 3-phosphate was blocked by AIBP substrate, NADPH (nicotinamide adenine dinucleotide phosphate), and both NADPH and silencing of Cdc42 interfered with the ability of AIBP to regulate lipid rafts and cholesterol efflux. Conclusions: Our findings indicate that an underlying mechanism of regulation of lipid rafts by AIBP involves PIP-dependent rearrangement of the cytoskeleton.

Abstract 1721: Deletion of Both Macrophage ABCG1 and ApoE Independently Promotes Atherosclerotic Lesion Development in LDL Receptor Knockout Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ruud Out ◽  
Bart Lammers ◽  
Reeni B. Hildebrand ◽  
Carmel M. Quinn ◽  
David Williamson ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Independent Effect ◽  
High Cholesterol Diet ◽  
Moderate Increase ◽  
Lesion Development ◽  
Macrophage Cholesterol Efflux ◽  
Atherosclerotic Lesion Development

Objective ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein E (apoE) play a role in macrophage cholesterol efflux and consequently the development of atherosclerosis. Although a possible interaction between ABCG1 and apoE in cholesterol efflux was postulated, the combined action of these proteins in atherosclerosis is still unclear. Methods and Results LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCG1/apoE double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls. After feeding a high-fat/high-cholesterol diet for 6 weeks, no differences were found in serum lipid levels. However, the mean atherosclerotic lesion area in dKO transplanted animals (187 ± 18 × 10 3 μ m 2 ) was 1.4-fold (p < 0.01) increased compared to single knockouts (ABCG1 KO: 138 ± 5 × 10 3 μm 2 ; apoE KO: 131 ± 7 × 10 3 μm 2 ) and 1.9-fold (p< 0.001) as compared to WT controls (97 ± 15 × 10 3 μm 2 ). In vitro cholesterol efflux experiments confirmed that combined deletion of ABCG1 and apoE resulted in a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts. Conclusions Deletion of macrophage ABCG1 or apoE does lead to a moderate increase in atherosclerotic lesion development while combined deletion of ABCG1 and apoE induces a more dramatic increase in atherosclerosis. These results indicate an added, independent effect for both macrophage ABCG1 and apoE in atherosclerosis.

scholarly journals An atherosclerotic plaque-targeted single-chain antibody for MR/NIR-II imaging of atherosclerosis and anti-atherosclerosis therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Liwei Zhang ◽  
Sheng Xue ◽  
Feng Ren ◽  
Siyang Huang ◽  
Ruizhi Zhou ◽  
...  
Keyword(s):  
Near Infrared ◽  
Oxidized Ldl ◽  
Macrophage Polarization ◽  
Noninvasive Imaging ◽  
Atherosclerotic Lesion ◽  
Scfv Antibody ◽  
Atherosclerotic Plaques ◽  
Single Chain ◽  
Single Chain Antibody ◽  
M1 Macrophage

Abstract Background Oxidation-specific epitopes (OSEs) are rich in atherosclerotic plaques. Innate and adaptive immune responses to OSEs play an important role in atherosclerosis. The purpose of this study was to develop novel human single-chain variable fragment (scFv) antibody specific to OSEs to image and inhibit atherosclerosis. Results Here, we screened a novel scFv antibody, named as ASA6, from phage-displayed human scFv library. ASA6 can bind to oxidized LDL (Ox-LDL) and atherosclerotic plaques. Meanwhile, ASA6 can also inhibit the uptake of Ox-LDL into macrophage to reduce macrophage apoptosis. The atherosclerotic lesion area of ApoE−/− mice administrated with ASA6 antibody was significantly reduced. Transcriptome analysis reveals the anti-atherosclerosis effect of ASA6 is related to the regulation of fatty acid metabolism and inhibition of M1 macrophage polarization. Moreover, we conjugated ASA6 antibody to NaNdF4@NaGdF4 nanoparticles for noninvasive imaging of atherosclerotic plaques by magnetic resonance (MR) and near-infrared window II (NIR-II) imaging. Conclusions Together, these data demonstrate the potential of ASA6 antibody in targeted therapy and noninvasive imaging for atherosclerosis. Graphic abstract

scholarly journals TNF-Like Ligand 1 Aberrance Aggravates Nonalcoholic Steatohepatitis via M1 Macrophage Polarization

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Yuxin Luo ◽  
Jinbo Guo ◽  
Wenxiu Jia ◽  
Mengyao Wu ◽  
Fengrong Yin ◽  
...  
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Lipid Accumulation ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Primary Biliary Cholangitis ◽  
M2 Macrophage ◽  
Hepatic Lipid Accumulation ◽  
High Fructose ◽  
M1 Macrophage

Nonalcoholic steatohepatitis (NASH) is a progressive, chronic liver disease worldwide which imposes a large economic burden on society. M1/M2 macrophage balance destruction and recruitment of mononuclear immune cells to the liver play critical roles in NASH. Several studies have shown that the expression of TNF-like ligand 1 aberrance (TL1A) increased in macrophages associated with many inflammatory diseases, for example, inflammatory bowel disease, primary biliary cholangitis, and liver fibrosis. One recent research showed that weight, abdominal adipose, and liver leptin, one of the critical fat cytokines, were reduced in TL1A knockout mice. However, the functional and molecular regulatory mechanisms of TL1A on macrophage polarization and recruitment in NASH have yet to be clarified. The authors found that high fructose high fat diet and methionine-choline deficiency diet induced the expression of TL1A in macrophages of liver tissue from murine NASH models. Myeloid-specific TL1A overexpressed mice showed exacerbated steatohepatitis with increased hepatic lipid accumulation, inflammation, liver injury, and apoptosis. M1 macrophages’ infiltration and the production of proinflammatory and chemotactic cytokines increased in liver of NASH mouse models with myeloid-specific TL1A overexpressed. Furthermore, this paper revealed that bone marrow-derived macrophages and Kupffer cells with overexpression of TL1A exacerbated the lipid accumulation and expression of proinflammatory factors in the murine primary hepatocytes after free fatty acid treatment in vitro. In conclusion, TL1A-mediated M1-type macrophage polarization and recruitment into the liver promoted steatohepatitis in murine NASH.

scholarly journals Inhibition of HIV Replication by Apolipoprotein A-I Binding Protein Targeting the Lipid Rafts

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Larisa Dubrovsky ◽  
Adam Ward ◽  
Soo-Ho Choi ◽  
Tatiana Pushkarsky ◽  
Beda Brichacek ◽  
...  
Keyword(s):  
T Cells ◽  
Lipid Rafts ◽  
Cell Fusion ◽  
Binding Protein ◽  
Rapid Progression ◽  
Inflammatory Factor ◽  
Hiv Disease ◽  
Hiv Replication ◽  
Apolipoprotein A ◽  
Hiv 1

ABSTRACT Apolipoprotein A-I binding protein (AIBP) is a protein involved in regulation of lipid rafts and cholesterol efflux. AIBP has been suggested to function as a protective factor under several sets of pathological conditions associated with increased abundance of lipid rafts, such as atherosclerosis and acute lung injury. Here, we show that exogenously added AIBP reduced the abundance of lipid rafts and inhibited HIV replication in vitro as well as in HIV-infected humanized mice, whereas knockdown of endogenous AIBP increased HIV replication. Endogenous AIBP was much more abundant in activated T cells than in monocyte-derived macrophages (MDMs), and exogenous AIBP was much less effective in T cells than in MDMs. AIBP inhibited virus-cell fusion, specifically targeting cells with lipid rafts mobilized by cell activation or Nef-containing exosomes. MDM-HIV fusion was sensitive to AIBP only in the presence of Nef provided by the virus or exosomes. Peripheral blood mononuclear cells from donors with the HLA-B*35 genotype, associated with rapid progression of HIV disease, bound less AIBP than cells from donors with other HLA genotypes and were not protected by AIBP from rapid HIV-1 replication. These results provide the first evidence for the role of Nef exosomes in regulating HIV-cell fusion by modifying lipid rafts and suggest that AIBP is an innate factor that restricts HIV replication by targeting lipid rafts. IMPORTANCE Apolipoprotein A-I binding protein (AIBP) is a recently identified innate anti-inflammatory factor. Here, we show that AIBP inhibited HIV replication by targeting lipid rafts and reducing virus-cell fusion. Importantly, AIBP selectively reduced levels of rafts on cells stimulated by an inflammatory stimulus or treated with extracellular vesicles containing HIV-1 protein Nef without affecting rafts on nonactivated cells. Accordingly, fusion of monocyte-derived macrophages with HIV was sensitive to AIBP only in the presence of Nef. Silencing of endogenous AIBP significantly upregulated HIV-1 replication. Interestingly, HIV-1 replication in cells from donors with the HLA-B*35 genotype, associated with rapid progression of HIV disease, was not inhibited by AIBP. These results suggest that AIBP is an innate anti-HIV factor that targets virus-cell fusion.

scholarly journals Characterizing the Role of Glycogen Synthase Kinase (GSK)-3α/β in Macrophage Polarization and the Regulation of Pro-Atherogenic Pathways

2021 ◽  
Author(s):  
Sarvatit Patel ◽  
Geoff Werstuck
Keyword(s):  
Inflammatory Response ◽  
Cell Viability ◽  
Lipid Accumulation ◽  
Glycogen Synthase ◽  
Macrophage Polarization ◽  
Density Lipoprotein ◽  
Myeloid Cell ◽  
Glycogen Synthase Kinase ◽  
Cellular Mechanisms ◽  
M1 Macrophage

Abstract The molecular and cellular mechanisms that link cardiovascular risk factors to the initiation and progression of atherosclerosis are not understood. Recent findings from our laboratory indicate that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3α/β induces pro-atherosclerotic pathways. The objective of this study was to define the specific roles of GSK3α and GSK3β in the activation of pro-atherogenic processes in macrophages. Bone marrow derived macrophages (BMDM) were isolated from low-density lipoprotein receptor knockout (Ldlr-/-) mice and Ldlr-/- mice with myeloid deficiency of GSK3α and/or GSK3β. M1 and M2 macrophages were used to examine functions relevant to the development of atherosclerosis, including polarization, inflammatory response, cell viability, lipid accumulation, migration, and metabolism. GSK3α deficiency impairs M1 macrophage polarization, and reduces the inflammatory response and lipid accumulation, but increases macrophage mobility/migration. GSK3β deficiency promotes M1 macrophage polarization, which further increases the inflammatory response and lipid accumulation, but decreases macrophage migration. Macrophages deficient in both GSK3α and GSK3β exhibit increased cell viability, proliferation, and metabolism. These studies begin to delineate the specific roles of GSK3α and GSK3β in macrophage polarization and function. These data suggest that myeloid cell GSK3α signaling regulates M1 macrophage polarization and pro-atherogenic functions to promote atherosclerosis development.

Abstract 19: Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Cameron McAlpine ◽  
Aric Huang ◽  
Abby Emdin ◽  
Nicole Banko ◽  
Daniel Beriault ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Atherosclerotic Lesion ◽  
M2 Macrophage ◽  
Lesion Volume ◽  
Macrophage Phenotype ◽  
Expression Of Genes ◽  
M1 Macrophage ◽  
Deficient Mice

Objective: Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diseases including diabetes, cancer, Alzheimer’s and atherosclerosis. The tissue and homolog specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell specific deletion of GSK3α or GSK3β on atherosclerosis in LDLR-/- mice. Approach and results: We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR-/- mice and mice were fed a high fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid deletion of GSK3α, but not GSK3β, reduced atherosclerotic lesion volume as well as lesion complexity. Mice lacking GSK3α in myeloid cells had a less inflammatory and more anti-inflammatory plasma cytokine profile. Macrophages within atherosclerotic lesions of myeloid GSK3α deficient mice, but not GSK3β deficient mice, displayed reduced expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Finally, bone marrow derived macrophages were isolated and differentiated into classical M1 macrophages or alternative M2 macrophages in vitro. GSK3α deletion, but not GSK3β deletion, attenuated the expression of genes associated with M1 polarization while promoting the expression of genes associated with M2 polarization. Mechanistically, GSK3α regulated macrophage polarization by modulating the phosphorylation and activation of STAT transcription factors. Conclusions: Our findings suggest that deletion of myeloid GSK3α attenuates the progression of atherosclerosis by regulating STAT activation and promoting an M2 macrophage phenotype.

scholarly journals CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRα pathway

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Gang Wang ◽  
Jiao-Jiao Chen ◽  
Wen-Yi Deng ◽  
Kun Ren ◽  
Shan-Hui Yin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cholesterol Efflux ◽  
Lentiviral Vector ◽  
Macrophage Polarization ◽  
Vascular Inflammation ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Novel Approach ◽  
Underlying Mechanisms

AbstractC1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.

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