Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy.
TL;DR: A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis.
About: This article is published in Progress in Lipid Research.The article was published on 2011-10-01. It has received 338 citations till now. The article focuses on the topics: LRP1 & LDL receptor.
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TL;DR: In this article, the authors found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation.
Abstract: Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation
762 citations
TL;DR: Molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with “inflammageing” or parainflammation are highlighted and suggested to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation.
Abstract: Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a pro-inflammatory phenotype has been called "inflamm-aging." Despite research there is no clear understanding about the causes of "inflamm-aging" that underpin most major age-related diseases, including atherosclerosis, diabetes, Alzheimer's disease, rheumatoid arthritis, cancer, and aging itself. While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. The age-related change in redox balance, the increase in age-related senescent cells, the senescence-associated secretory phenotype (SASP) and the decline in effective autophagy that can trigger the inflammasome, suggest that it may be possible to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation. Conversely there may be learning from molecular or genetic pathways from long-lived cohorts who exemplify good quality aging. Here, we will discuss some of the current ideas and highlight molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with "inflammageing" or parainflammation. Evidence of these findings will be drawn from research in cardiovascular disease, cancer, neurological inflammation and rheumatoid arthritis.
663 citations
Cites background from "Cytokines, macrophage lipid metabol..."
...In response to increased low-density lipoprotein (LDL), hypertension, and subsequent shear stress, cytokines modulate endothelial cell permeability and recruit monocytes and T-lymphocytes (344, 345)....
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01 Sep 2014
TL;DR: It is found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation.
Abstract: Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.
507 citations
TL;DR: Key signaling pathways are presented to provide a context for the gene manipulations summarized herein and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.
Abstract: At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-α and related family members leading to activation of NF-κB; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.
442 citations
Cites background from "Cytokines, macrophage lipid metabol..."
...Dual delivery of both STAT3 and IL-10 were not additive in their antiatherosclerotic effects (252)....
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...Macrophages produced more TNF- upon stimulation and less anti-inflammatory IL-10 (881)....
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...They also contribute to enhanced foam cell formation by downregulation of cholesterol efflux (1174)....
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...TNFR2 / apoE / 243% TNFR2 / apoE / mice had twofold elevations in plasma TNFand IL-17 (possibly inflammatory) and IL-10 (antiinflammatory)....
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...These include TGF- and IL-10 (1174) to some extent, but more specifically IL-33 binding to its receptor ST2L on macrophages (1175)....
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TL;DR: The current understanding of the roles of different cytokines in atherosclerosis together with therapeutic approaches aimed at manipulating their actions are described.
380 citations
Cites background from "Cytokines, macrophage lipid metabol..."
...hypertension and toxins from cigarette smoke [2]....
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...as an inflammatory disorder of medium and large arteries initiated by risk factors such as high plasma cholesterol levels and hypertension [2]....
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...The normal function of monocyte recruitment in inflammation is to participate in its resolution in order to ultimately decrease further entry of immune cells, cause egress of existing cells from inflammatory sites and efferocytosis of apoptotic cells [2,14]....
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...phages or dendritic cells (DCs) depending on the cytokine signal received with macrophage colony-stimulating factor (M-CSF) a major facilitator of macrophage differentiation [2]....
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...Cytokines can modulate EC permeability [2,3]....
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References
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TL;DR: Atherosclerosis is an inflammatory disease as discussed by the authors, and it is a major cause of death in the United States, Europe, and much of Asia, despite changes in lifestyle and use of new pharmacologic approaches to lower plasma cholesterol concentrations.
Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .
19,881 citations
Journal Article•
TL;DR: Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations, cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.
9,749 citations
TL;DR: This Review suggests a new grouping of macrophages based on three different homeostatic activities — host defence, wound healing and immune regulation, and proposes that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation.
Abstract: Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.
7,384 citations
TL;DR: Patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes mellitus as well as the availability of outcome data for myocardial infarction and death from cardiovascular causes.
Abstract: �Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.
4,570 citations
St George's Hospital1, University of Cologne2, University of Perugia3, Takeda Pharmaceutical Company4, University of Nottingham5, Eli Lilly and Company6, International Diabetes Federation7, University of Edinburgh8, University of Gothenburg9, University College London10, University of Oslo11, Geneva College12, VU University Amsterdam13, Comenius University in Bratislava14, University of Liège15, University of Düsseldorf16, Aarhus University17
TL;DR: Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified; mortality rates from heart failure did not differ between groups.
3,899 citations