scholarly journals Activation of NLRP3 inflammasome by cholesterol crystals in alcohol consumption induces atherosclerotic lesions

2017 ◽  
Vol 62 ◽  
pp. 291-305 ◽  
Author(s):  
P.M. Abdul-Muneer ◽  
Saleena Alikunju ◽  
Vikas Mishra ◽  
Heather Schuetz ◽  
Adam M. Szlachetka ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Nlrp3 Inflammasome ◽  
Cholesterol Crystals ◽  
Atherosclerotic Lesions

scholarly journals Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

PLoS ONE ◽  
2010 ◽  
Vol 5 (7) ◽  
pp. e11765 ◽  
Author(s):  
Kristiina Rajamäki ◽  
Jani Lappalainen ◽  
Katariina Öörni ◽  
Elina Välimäki ◽  
Sampsa Matikainen ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cholesterol Metabolism ◽  
Cholesterol Crystals ◽  
Human Macrophages

scholarly journals Melatonin Ameliorates the Progression of Atherosclerosis via Mitophagy Activation and NLRP3 Inflammasome Inhibition

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Sai Ma ◽  
Jiangwei Chen ◽  
Jing Feng ◽  
Ran Zhang ◽  
Miaomiao Fan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Ros Scavenging ◽  
Atherosclerotic Lesions ◽  
Autophagy Inhibitor ◽  
Nlrp3 Inflammasome Activation ◽  
Progression Of Atherosclerosis

The NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediated inflammatory responses are critically involved in the progression of atherosclerosis (AS), which is the essential cause for cardiovascular diseases. Melatonin has anti-inflammatory properties. However, little is known about the potential effects of melatonin in the pathological process of AS. Herein, we demonstrate that melatonin suppressed prolonged NLRP3 inflammasome activation in atherosclerotic lesions by reactive oxygen species (ROS) scavenging via mitophagy in macrophages. The atherosclerotic mouse model was induced with a high-fat diet using ApoE−/− mice. Melatonin treatment markedly attenuated AS plaque size and vulnerability. Furthermore, melatonin decreased NLRP3 inflammasome activation and the consequent IL-1β secretion within atherosclerotic lesions. Despite the unchanged protein expression, the silent information regulator 3 (Sirt3) activity was elevated in the atherosclerotic lesions in melatonin-treated mice. In ox-LDL-treated macrophages, melatonin attenuated the NLRP3 inflammasome activation and the inflammatory factors secretion, while this protective effect was abolished by either Sirt3 silence or autophagy inhibitor 3-MA. Mitochondrial ROS (mitoROS), which was a recognized inducer for NLRP3 inflammasome, was attenuated by melatonin through the induction of mitophagy. Both Sirt3-siRNA and autophagy inhibitor 3-MA partially abolished the beneficial effects of melatonin on mitoROS clearance and NLRP3 inflammasome activation, indicating the crucial role of Sirt3-mediated mitophagy. Furthermore, we demonstrated that melatonin protected against AS via the Sirt3/FOXO3a/Parkin signaling pathway. In conclusion, the current study demonstrated that melatonin prevented atherosclerotic progression, at least in part, via inducing mitophagy and attenuating NLRP3 inflammasome activation, which was mediated by the Sirt3/FOXO3a/Parkin signaling pathway. Collectively, our study provides insight into melatonin as a new target for therapeutic intervention for AS.

scholarly journals MECHANISMS OF ATHEROGENESIS AND ITS INTENSIFICATION IN PATIENTS WITH RHEUMATOID ARTHRITIS

2020 ◽  
pp. 8-24
Author(s):  
V. K. Kazymyrko ◽  
L. N. Ivanitska ◽  
T. S. Silantyeva ◽  
A. G. Dubkova ◽  
V. V. Kutovoy
Keyword(s):  
Immune Complexes ◽  
Protein Complexes ◽  
Cell Damage ◽  
Cholesterol Crystals ◽  
Atherosclerotic Lesions ◽  
Arterial Lesions ◽  
Tnf Α ◽  
Traditional Risk Factors ◽  
Mechanisms Of Development

The article describes the role of cholesterol crystals (CS) in the mechanisms of development in the inner lining of arteries of inflammation – granulomatosis, induced by foreign bodies. The smallest CS crystals are found already in early atherosclerotic lesions. They are a factor in the initiation and exacerbation of atherosclerosis (At), cause cell damage and apoptosis. The formation of crystals within the necrotic nuclei of plaques can lead to an increase in their volume and to rupture. It has been shown that damage to the membranes of macrophages phagolysosomes by absorbed CS crystals leads to the inclusion of protein complexes – inflammasomes – in the inflammatory process, which trigger the inflammatory signaling cascade and are responsible for the secretion of pro-inflammatory cytokines. Inflammasomes NLRP3 are necessary for the process of atherogenesis; their activation is a link between the metabolism of cholesterol and inflammation involving macrophages. Unlike At, RA is manifested by autoimmune inflammation and immunocomplex vasculitis. When these diseases are combined, the effects of proinflammatory cytokines add up, an increase in the severity of inflammation, increased tissue damage and progression of atherosclerotic arterial lesions. The accelerated development of At in RA patients is facilitated by a combination of the action of traditional risk factors for atherogenesis and damage to the walls (endothelium) of arteries by immune complexes, complement, neutrophils and lymphocytes with an increase in their permeability to the lipid factor. The deposition of immune complexes in the capillaries of plaques leads to damage to their walls, destabilization of plaques and the development of acute cardiovascular events. The intensification of lipid accumulation and inflammation in the plaques of RA patients is confirmed in the section. Anticytokine drugs, primarily TNF-α and IL-1β antagonists, are pathogenetically substantiated agents for the progression of At in patients with RA. Statins remain a widely used class of drugs. They, in addition to hypolipidemic, immunomodulatory and anti-inflammatory effects, affect the crystallization of cholesterol, dissolve crystals and stabilize plaques.

scholarly journals Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis

2020 ◽  
Author(s):  
Ada Admin ◽  
Arpeeta Sharma ◽  
Judy S.Y. Choi ◽  
Nada Stefanovic ◽  
Annas-Al Sharea ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Vascular Function ◽  
Vascular Complications ◽  
Fold Increase ◽  
Low Grade ◽  
Murine Bone Marrow ◽  
Fibrous Cap ◽  
Atherosclerotic Lesions ◽  
Persistent Inflammation ◽  
Fibrous Cap Thickness

Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the NLRP3-inflammasome to trigger the maturation and release of the inflammatory cytokine interleukin-1β (IL-1β). We investigated whether inhibiting the NLRP3-inflammasome, through the use of the specific small-molecule NLRP3 inhibitor, MCC950, could reduce inflammation, improve vascular function and protect against diabetes-associated atherosclerosis in the streptozotocin (STZ)-induced diabetic Apolipoprotein knockout (ApoE<sup>-/-</sup>) mouse. Diabetes led to a ~4-fold increase in atherosclerotic lesions throughout the aorta, which were significantly attenuated with MCC950 (<i>P</i><0.001). This reduction in lesions was associated with decreased monocyte-macrophage content, reduced necrotic core, attenuated inflammatory gene expression (Il-1β, TNFα, ICAM-1, MCP-1, <i>P</i><0.05) and reduced oxidative stress, whilst maintaining fibrous cap thickness. Additionally, vascular function was improved in diabetic vessels of mice treated with MCC950 (<i>P</i><0.05). In a range of cell lines (murine bone marrow-derived macrophages (BMDMs), human monocytic THP-1 cells, PMA-differentiated human macrophages and diabetic human aortic smooth muscle cells (AoSMCs)), MCC950 significantly reduced IL-1β and/or caspase-1 secretion and attenuated leukocyte-SMC interactions under high glucose or LPS conditions. In summary, MCC950 reduces plaque development, promotes plaque stability and improves vascular function, suggesting that targeting NLRP3-mediated inflammation is a novel therapeutic strategy to improve diabetes-associated vascular disease.

scholarly journals The Role of Colchicine in Acute Coronary Syndrome

2020 ◽  
Vol 1 (4) ◽  
pp. 4-8
Author(s):  
Liemena Harold Adrian ◽  
Budi Satrijo ◽  
Djanggan Sargowo ◽  
Indra Prasetya
Keyword(s):  
Acute Coronary Syndrome ◽  
Systemic Inflammation ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Inflammatory Pathway ◽  
Cholesterol Crystals ◽  
Inflammatory Cascade ◽  
Coronary Syndrome ◽  
Subsequent Activation

Background: Despite the advances of current optimal treatment of atherosclerotic disease, the incidence of events after acute coronary syndrome (ACS) remains high. Colchicine, with its well-established pleiotropic anti-inflam- matory effects, may inhibit NLRP3 inflammasome, a key mediator in atherosclerosis-associated inflammation (AAI) thus reducing systemic inflammation. NRLP3 inflammasome activation inside leukocytes (mainly monocytes and neutrophils) is precipitated by cholesterol crystals that are present in all atherosclerosis stages. 􏰟􏰋􏰡􏰈􏰇􏱎􏰋􏰇􏰆􏰂 􏰍􏰀􏰂􏰅􏰩􏰍􏰂􏰅􏰃􏰆 􏰃􏰜 􏰢􏰎􏰃􏰐􏰅􏰆􏰜􏰏􏰍􏰝􏰝􏰍􏰂􏰃􏰎􏰁 􏰀􏰁􏰂􏰃􏰄􏰅􏰆􏰇􏰈 􏰈􏰋􏰀􏰌 􏰍􏰈 􏰅􏰆􏰂􏰇􏰎􏰏􏰇􏰋􏰄􏰅􏰆􏰐􏰑􏰒 􏰍􏰆􏰗 􏰅􏰆􏰂􏰇􏰎􏰏􏰇􏰋􏰄􏰅􏰆􏰐􏰑􏰣 􏰳􏰅􏰏􏰏 􏰜􏰃􏰏􏰏􏰃􏰳􏰨 􏰘􏰌􏰇􏰈􏰇 cytokines are the crucial inflammatory pathway mediators that promote the formation of plaque and instability in the inflammatory cascade. Objective: This review will elaborate on the function of immune cells in atherosclerosis, explain the mechanisms of NLRP3 inflammasome activation in the context of AAI, and address the possible role of colchicine specifically targeting NLRP3 inflammasome and its concomitant downstream mediators in ACS, and provide an overview of current or ongoing studies produced in this area. Discussion : NRLP3 inflammasome activation inside leukocytes (mainly monocytes and neutrophils) is precipitat- ed by cholesterol crystals that are present in all atherosclerosis stages. Subsequent activation of pro-inflammatory pathway mediators that promote the formation of plaque and instability in the inflammatory cascade. A potential advantage of a medication acting through an inflammatory milieu found in atherosclerotic lesions has recently become the need for novel therapeutic options. Colchicine, with its well-established pleiotropic anti-inflammato- ry effects, may inhibit NLRP3 inflammasome, a key mediator in atherosclerosis-associated inflammation (AAI) thus reducing systemic inflammation. Conclusion: Colchicine is a safe and reliable medication for ACS patients, alongside reveal various benefit in reducing inflammation through inhibition of NLRP3 Inflammasome`

Cholesterol crystals activate the NLRP3 inflammasome in human monocytes and macrophages

2010 ◽  
Vol 163 ◽  
pp. S27-S28 ◽  
Author(s):  
K. Rajamäki ◽  
J. Lappalainen ◽  
K. Öörni ◽  
E. Välimäki ◽  
S. Matikainen ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Human Monocytes ◽  
Cholesterol Crystals ◽  
Monocytes And Macrophages ◽  
Human Monocytes And Macrophages

scholarly journals The Purinergic P2X7 Receptor-NLRP3 Inflammasome Pathway: A New Target in Alcoholic Liver Disease?

2021 ◽  
Vol 22 (4) ◽  
pp. 2139
Author(s):  
Brendan Le Daré ◽  
Pierre-Jean Ferron ◽  
Thomas Gicquel
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Alcoholic Liver Disease ◽  
Kupffer Cells ◽  
Nlrp3 Inflammasome ◽  
Liver Diseases ◽  
Current Knowledge ◽  
Purinergic Signaling ◽  
World Health ◽  
Alcoholic Liver Diseases

The World Health Organization has estimated that approximately 3 million deaths are attributable to alcohol consumption each year. Alcohol consumption is notably associated with the development and/or progression of many non-communicable inflammatory diseases—particularly in the liver. Although these alcoholic liver diseases were initially thought to be caused by the toxicity of ethanol on hepatocytes, the latest research indicates Kupffer cells (the liver macrophages) are at the heart of this “inflammatory shift”. Purinergic signaling (notably through P2X7 receptors and the NLRP3 inflammasome) by Kupffer cells appears to be a decisive factor in the pathophysiology of alcoholic liver disease. Hence, the modulation of purinergic signaling might represent a new means of treating alcoholic liver disease. Here, we review current knowledge on the pathophysiology of alcoholic liver diseases and therapeutic perspectives for targeting these inflammatory pathways.

scholarly journals Colchicine Alleviates Cholesterol Crystal-Induced Endothelial Cell Pyroptosis through Activating AMPK/SIRT1 Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-18 ◽  
Author(s):  
Mengyue Yang ◽  
Hang Lv ◽  
Qi Liu ◽  
Lu Zhang ◽  
Ruoxi Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cardiovascular Diseases ◽  
Nlrp3 Inflammasome ◽  
Cell Injury ◽  
Inflammatory Factors ◽  
Acute Gout ◽  
Cholesterol Crystal ◽  
Cholesterol Crystals ◽  
Related Proteins

Cholesterol crystal- (CC-) induced endothelial cell inflammation and pyroptosis play an important role in the development of cardiovascular diseases, especially in atherosclerosis (AS). Increasing evidence suggests that cholesterol crystals are known to be a pivotal pathological marker of atherosclerotic plaque vulnerability. As a classical nonspecific anti-inflammatory drug, colchicine has been widely used in the treatment of acute gout. However, whether colchicine could alleviate CC-induced endothelial cell injury and the related mechanisms remains to be addressed. In this study, the protective effect of colchicine on human umbilical vein endothelial cells (HUVECs) was confirmed. Our results revealed that after cotreatment with colchicine and cholesterol crystals in endothelial cells, the uptake of cholesterol crystals was significantly decreased, the cell viability was obviously increased, and the release of lactate dehydrogenase (LDH) and the number of pyroptotic cells decreased significantly; then, the expression of NLRP3 inflammasome-related proteins and various inflammatory factors was also visibly suppressed; moreover, as a potent activator of NLRP3 inflammasome, the intracellular ROS level was clearly reduced, while mitochondrial membrane potential improved significantly. In addition, the expression levels of AMP-dependent kinase (AMPK) pathway-related proteins as well as various antioxidant enzymes were elevated notably in varying degrees. However, the above effects of colchicine were completely offset by the treatment of siRNA targeting AMPKα and Sirtuin1 (SIRT1). Therefore, we conclude that colchicine plays a crucial role in alleviating the intracellular inflammatory response and NLRP3 inflammation activation, attenuating the levels of cellular oxidative stress and pyroptosis in endothelial cells via regulating AMPK/SIRT1 signaling, which may be a concrete mechanism for the secondary prevention of cardiovascular diseases.

scholarly journals Cholesterol crystals of atherosclerotic lesions induce endothelial dysfunction via RhoA activation

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Yvonne Baumer ◽  
Svenja Meiler ◽  
Pavlos Anastasiadis ◽  
John Allen ◽  
William A. Boisvert
Keyword(s):  
Endothelial Dysfunction ◽  
Cholesterol Crystals ◽  
Rhoa Activation ◽  
Atherosclerotic Lesions
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