Abstract 43: Cholesterol Efflux Pathways Suppress Inflammasome Activation in Mice and Humans

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Marit Westerterp ◽  
Panagiotis Fotakis ◽  
Mireille Ouimet ◽  
Andrea E Bochem ◽  
Hanrui Zhang ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Loss Of Function ◽  
Caspase 1 ◽  
Macrophage Cholesterol Efflux

Plasma high-density-lipoprotein (HDL) has several anti-atherogenic properties, including its key role in functioning as acceptor for ATP-binding cassette A1 and G1 (ABCA1 and ABCG1) mediated cholesterol efflux. We have shown previously that macrophage Abca1/g1 deficiency accelerates atherosclerosis, by enhancing foam cell formation and inflammatory cytokine expression in atherosclerotic plaques. Macrophage cholesterol accumulation activates the inflammasome, leading to caspase-1 cleavage, required for IL-1β and IL-18 secretion. Several studies have suggested that inflammasome activation accelerates atherogenesis. We hypothesized that macrophage Abca1/g1 deficiency activates the inflammasome. In Ldlr -/- mice fed a Western type diet (WTD), macrophage Abca1/g1 deficiency increased IL-1β and IL-18 plasma levels (2-fold; P <0.001), and induced caspase-1 cleavage. Deficiency of the inflammasome components Nlrp3 or caspase-1 in macrophage Abca1/g1 knockouts reversed the increase in plasma IL-18 levels ( P <0.001), indicating these changes were inflammasome dependent. We found that macrophage Abca1/g1 deficiency induced caspase-1 cleavage in splenic CD115 + monocytes and CD11b + macrophages. While mitochondrial ROS production or lysosomal function were not affected, macrophage Abca1/g1 deficiency led to an increased splenic population of monocytes (2.5-fold; P <0.01). Monocytes secrete ATP, and as a result, ATP secretion from total splenic cells was increased (2.5-fold; P <0.01), likely contributing to inflammasome activation. Caspase-1 deficiency decreased atherosclerosis in macrophage Abca1/g1 deficient Ldlr -/- mice fed WTD for 8 weeks (225822 vs 138606 μm 2 ; P <0.05). Of therapeutic interest, one injection of reconstituted HDL (100 mg/kg) in macrophage Abca1/g1 knockouts decreased plasma IL-18 levels ( P <0.05). Tangier disease patients, with a homozygous loss-of-function for ABCA1, showed increased IL-1β and IL-18 plasma levels (3-fold; P <0.001), suggesting that cholesterol efflux pathways also suppress inflammasome activation in humans. These findings suggest that macrophage cholesterol efflux pathways suppress inflammasome activation, possibly contributing to the anti-atherogenic effects of HDL treatment.

scholarly journals TRPM2 deficiency protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages

2021 ◽  
Author(s):  
Pengyu Zong ◽  
Jianlin Feng ◽  
Zhichao Yue ◽  
Albert S. Yu ◽  
Yasuo Mori ◽  
...  
Keyword(s):  
Foam Cell ◽  
Heart Diseases ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Macrophage Infiltration ◽  
Plaque Burden ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Monocyte Chemoattractant Protein 1

Atherosclerosis is the major cause of ischemic heart diseases and ischemic brain stroke, which are the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes remain unclear. Here we show that oxidative stress-activated Ca2+-permeable TRPM2 plays a key role in the pathogenesis of atherosclerosis. Trpm2 deletion produces a potent protective effect against atherosclerosis in ApoE-/- mice fed with a high-fat diet (HFD), as evidenced by reduced atherosclerotic plaque burden, decreased macrophage load and suppressed inflammasome activation in the vessel wall. Moreover, we show that Trpm2 deletion or inhibition reduces oxidized low-density lipoprotein (oxLDL) uptake by macrophages, suppresses macrophage infiltration induced by monocyte chemoattractant protein-1 (MCP1), and prevents the impairment of macrophage emigration caused by oxLDL. Intriguingly, we uncover that activation of CD36, an oxLDL receptor, can promote the activation of TRPM2, and vice versa, the CD36-mediated inflammatory cascade in atherosclerosis is dependent on TRPM2. In transfected HEK293T cells, CD36 ligands oxLDL and TSP1 induce TRPM2 activation in a CD36-dependent manner. Deleting Trpm2 or inhibiting TRPM2 activity in cultured macrophages suppresses the CD36 signaling cascade induced by oxLDL and TSP1. Our studies establish TRPM2-CD36 axis as a new mechanism underlying atherogenesis, and suggest TRPM2 as an effective therapeutic target for atherosclerosis.

scholarly journals ‘Blow my mind(in)’ – mindin neutralization for the prevention of atherosclerosis?

2018 ◽  
Vol 132 (14) ◽  
pp. 1509-1512
Author(s):  
Neil MacRitchie ◽  
Pasquale Maffia
Keyword(s):  
Vessel Wall ◽  
Cholesterol Efflux ◽  
Matrix Protein ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Extracellular Matrix Protein ◽  
Foam Cell Formation ◽  
Protective Effects ◽  
Inflammatory Microenvironment

The hallmark features of atherosclerosis include accumulation of low-density lipoprotein (LDL) carrying cholesterol in the vessel wall, formation of lipid-laden foam cells, and the creation of a pro-inflammatory microenvironment. To date, no effective treatments are clinically available for increasing cholesterol efflux from vascular macrophages and inducing reverse cholesterol transport (RCT). In an article published recently in Clinical Science (vol 132, issue 6, 1199-1213), Zhang and colleagues identified the extracellular matrix protein mindin/spondin 2 as a positive regulator of atherosclerosis. Genetic knockout of mindin in apolipoprotein-E (apoE)−/− mice attenuated atherosclerosis, foam cell formation, and inflammation within the vessel wall. Conversely, selective overexpression of mindin in macrophages in apoE−/− mice was sufficient to promote the greater severity of atherosclerosis. Interestingly, foam cell formation was closely associated with the expression of cholesterol transporters (ABCA1 and ACBG1) that facilitate cholesterol efflux. Liver X receptor (LXR)-β is a key modulator of cholesterol transporter expression and formed direct interactions with mindin. Furthermore, the protective effects of mindin deficiency on foam cell formation were blocked by inhibition of LXR-β. This article highlights a novel role of mindin in modulating foam cell formation and atherosclerosis development in mice through direct regulation of LXR-β. Thus far, direct targetting of LXR-β via pharmacological agonists has proven to be problematic due to the lack of subtype selective inhibitors and associated adverse effects. Indirect targetting of LXR-β, therefore, via mindin inhibition offers a new therapeutic strategy for increasing LXR-β induced cholesterol efflux, reducing foam cell formation, and preventing or treating atherosclerosis.

Abstract 168: The Acceleration of Foam Cell Formation by Chlamydia Pneumoniae Requires Nlrp3 Inflammasome Activation and Il-1 Signaling

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Gantsetseg Tumurkhuu ◽  
Jargalsaikhan Dagvadorj ◽  
Timothy R Crother ◽  
Kenichi Shimada ◽  
Moshe Arditi ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cholesterol Efflux ◽  
Molecular Mechanisms ◽  
Chlamydia Pneumoniae ◽  
Foam Cell ◽  
Cell Formation ◽  
Peritoneal Macrophages ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Abca1 Expression

Background & Objective: Foam cell formation (FCF) due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis. Chlamydia pneumoniae (Cp) promotes FCF in the presence of oxLDL, but the exact molecular mechanisms are still not completely delineated. Recent data indicates that the Nlrp3 inflammasome plays an important role in the formation of atherosclerotic plaques. Here we investigated the role of the Nlrp3 inflammasome during the acceleration of FCF by Cp infection. Methods and Results: In order to determine if the NLRP3 inflammasome played a role in Cp infection induced acceleration of FCF, we treated resident peritoneal macrophages exposed to oxLDL and Cp with the IL-1R antagonist, Anakinra, to block IL-1 signaling. Treatment with Anakinra resulted in a significant reduction in FCF. Nlrp3-/-, Casp1-/-, and WT macrophages were also treated with live Cp in the presence or absence of oxLDL. We found that Nlrp3-/- and Casp1-/- macrophages had significantly less FCF compared with WT cells. Interestingly, both ABCA1 (cholesterol efflux transporter) and its transcription factor, liver X receptor (LXR-α), were increased in Nlrp3-/- and Casp1-/- macrophages compared with WT cells. Addition of rIL-1β to Nlrp3-/- macrophages led to a decrease in ABCA1 expression and greater FCF. Importantly, Il1r-/- macrophages also had greater ABCA1 expression and reduced FCF when exposed to oxLDL and Cp infection. Conclusion: These data suggest that Cp infection facilitates foam cell formation in the presence of oxLDL by producing NLRP3 dependent IL-1 cytokines, which then feed back on the macrophages and interferes with cholesterol efflux by negatively regulating ABCA1. In the absence of IL-1 signaling, the expression of ABCA1 is upregulated leading to greater cholesterol efflux and reduced FCF. Thus we have identified a novel regulatory loop controlling FCF. Understanding these interacting pathways will lead to new therapeutic strategies against atherosclerosis.

Abstract 42: Control of Macrophage Cholesterol Efflux and Atherogenesis by the Noncoding RNA MeXis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Tamer Sallam ◽  
Marius Jones ◽  
Brandon J Thomas ◽  
Xiaohui Wu ◽  
Thomas Gilliland ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Noncoding Rna ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Therapeutic Approaches ◽  
Chromosome Architecture ◽  
Expression Of Genes ◽  
Macrophage Cholesterol Efflux

The ligand-dependent nuclear receptor LXR regulates the expression of genes involved in responses to excess cholesterol including Abca1. Macrophage-specific cholesterol efflux driven by Abca1 has been causally linked to the prevention and reversal of heart disease, but therapeutic strategies for targeting efflux pathways in macrophages have been elusive. Here, we define a novel regulatory axis controlling macrophage responses to cholesterol overload. We identify the lncRNA MeXis as an amplifier of LXR-dependent Abca1 gene transcription in macrophages. MeXis interacts with and guides the promoter binding of nuclear receptor transcriptional coactivators. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings identify MeXis as a transcriptional gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. It is conceivable that therapeutic approaches that enhance MeXis activity might augment reverse cholesterol transport and reduce foam cell formation.

scholarly journals Pharmacological Suppression of Hepcidin Increases Macrophage Cholesterol Efflux and Reduces Foam Cell Formation and Atherosclerosis

2012 ◽  
Vol 32 (2) ◽  
pp. 299-307 ◽  
Author(s):  
Omar Saeed ◽  
Fumiyuki Otsuka ◽  
Rohini Polavarapu ◽  
Vinit Karmali ◽  
Daiana Weiss ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Macrophage Cholesterol Efflux

scholarly journals Cholesterol Efflux Capacity of Apolipoprotein A-I Varies with the Extent of Differentiation and Foam Cell Formation of THP-1 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Kouji Yano ◽  
Ryunosuke Ohkawa ◽  
Megumi Sato ◽  
Akira Yoshimoto ◽  
Naoya Ichimura ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Capacity Measurement ◽  
Cholesterol Efflux Capacity ◽  
Apolipoprotein A ◽  
Significant Difference ◽  
Main Protein

Apolipoprotein A-I (apoA-I), the main protein component of high-density lipoprotein (HDL), has many protective functions against atherosclerosis, one of them being cholesterol efflux capacity. Although cholesterol efflux capacity measurement is suggested to be a key biomarker for evaluating the risk of development of atherosclerosis, the assay has not been optimized till date. This study aims at investigating the effect of different states of cells on the cholesterol efflux capacity. We also studied the effect of apoA-I modification by homocysteine, a risk factor for atherosclerosis, on cholesterol efflux capacity in different states of cells. The cholesterol efflux capacity of apoA-I was greatly influenced by the extent of differentiation of THP-1 cells and attenuated by excessive foam cell formation.N-Homocysteinylated apoA-I indicated a lower cholesterol efflux capacity than normal apoA-I in the optimized condition, whereas no significant difference was observed in the cholesterol efflux capacity between apoA-I in the excessive cell differentiation or foam cell formation states. These results suggest that cholesterol efflux capacity of apoA-I varies depending on the state of cells. Therefore, the cholesterol efflux assay should be performed using protocols optimized according to the objective of the experiment.

scholarly journals Naoxintong Retards Atherosclerosis by Inhibiting Foam Cell Formation Through Activating Pparα Pathway

2019 ◽  
Vol 18 (10) ◽  
pp. 698-710 ◽  
Author(s):  
Zeng Wang ◽  
Huairui Shi ◽  
Huan Zhao ◽  
Zhen Dong ◽  
Buchang Zhao ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Oxidized Low Density Lipoprotein ◽  
Beneficial Effects ◽  
Cell Accumulation ◽  
Ldl Uptake

Background: We recently reported that Naoxintong (NXT), a China Food and Drug Administration (FDA)-approved cardiac medicine, could reduce the plaque size, but the underlying mechanism remains elusive now. Objective: In this study, we investigated the effects of NXT on foam cell accumulation both in vivo and in vitro and explored related mechanisms. Method: THP-1 cells and bone marrow-derived macrophages were incubated with oxidized low-density lipoprotein (ox-LDL) with/without Naoxintong. ApoE-/- mice fed an atherogenic diet were administered to receive NXT for eight weeks. Macrophage-derived foam cell formation in plaques was measured by immunohistochemical staining. Expression of proteins was evaluated by Western blot. Lentivirus was used to knockdown PPARα in THP-1 cells. Results: After NXT treatment, foam cell accumulation was significantly reduced in atherosclerotic plaques. Further investigation revealed that oxidized low-density lipoprotein (ox-LDL) uptake was significantly decreased and expression of scavenger receptor class A (SR-A) and class B (SR-B and CD36) was significantly downregulated post-NXT treatment. On the other hand, NXT increased cholesterol efflux and upregulated ATP-binding cassette (ABC) transporters (ABCA-1 and ABCG-1) in macrophages. Above beneficial effects of NXT were partly abolished after lentiviral knockdown of PPARα. Conclusion: Our findings suggest that NXT could retard atherosclerosis by inhibiting foam cell formation through reducing ox-LDL uptake and enhancing cholesterol efflux and above beneficial effects are partly mediated through PPARα pathway.

scholarly journals Association of Electronegative LDL with Macrophage Foam Cell Formation and CD11c Expression in Rheumatoid Arthritis Patients

2020 ◽  
Vol 21 (16) ◽  
pp. 5883 ◽  
Author(s):  
Ching-Kun Chang ◽  
Po-Ku Chen ◽  
Joung-Liang Lan ◽  
Shih-Hsin Chang ◽  
Tsu-Yi Hsieh ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Plasma Levels ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Magnetic Bead ◽  
Treated Group ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Expression Levels

L5, the most negatively charged subfraction of low-density lipoprotein (LDL), is implicated in atherogenesis, but the pathogenic association is relatively unexplored in patients with rheumatoid arthritis (RA). We examined the role of L5 LDL in macrophage foam cell formation and the association of L5 with CD11c expression in THP-1 cells and RA patients. Using quantitative real-time PCR, we determined mRNA expression levels of ITGAX, the gene for CD11c, a marker associated with vascular plaque formation and M1 macrophages in atherogenesis, in 93 RA patients. We also examined CD11c expression on THP-1 cells treated with L5 by flow cytometry analysis and the plasma levels of inflammatory mediators using a magnetic bead array. We found a dose-dependent upregulation of foam cell formation of macrophages after L5 treatment (mean ± SEM, 12.05 ± 2.35% in L5 (10 µg/mL); 50.13 ± 3.9% in L5 (25 µg/mL); 90.69 ± 1.82% in L5 (50 µg/mL), p < 0.01). Significantly higher levels of CD11c expression were observed in 30 patients with a high percentage of L5 in LDL (L5%) (0.0752 ± 0.0139-fold) compared to 63 patients with normal L5% (0.0446 ± 0.0054-fold, p < 0.05). CD11c expression levels were increased in the L5-treated group (30.00 ± 3.13% in L5 (10 µg/mL); 41.46 ± 2.77% in L5 (50 µg/mL), p < 0.05) and were positively correlated with plasma levels of interleukin (IL)-6 and IL-8. L5 augmented the expression of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) on monocytes and macrophages. Our findings suggest that L5 may promote atherogenesis by augmenting macrophage foam cell formation, upregulating CD11c expression, and enhancing the expression levels of atherosclerosis-related mediators.

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