Immune-Inflammatory Responses in Atherosclerosis: The Role of Myeloid Cells

Inflammation plays a key role in the initiation and progression of atherosclerosis and can be caused by multiple agents, including increased concentration of circulating low-density lipoprotein (LDL) cholesterol. Areas of the arterial wall affected by atherosclerosis are enriched with lymphocytes and dendritic cells (DCs). Atherosclerotic plaques contain a variety of proinflammatory immune cells, such as macrophages, DCs, T cells, natural killer cells, neutrophils and others. Intracellular lipid accumulation in atherosclerotic plaque leads to formation of so-called foam cells, the cytoplasm of which is filled with lipid droplets. According to current understanding, these cells can also derive from the immune cells that engulf lipids by means of phagocytosis. Macrophages play a crucial role in the initial stages of atherogenesis by engulfing oxidized LDL (oxLDL) in the intima that leads to their transformation to foam cells. Dying macrophages inside the plaque form a necrotic core that further aggravates the lesion. Proinflammatory DCs prime differentiation of naïve T cells to proinflammatory Th1 and Th17 subsets. In this review, we discuss the roles of cell types of myeloid origin in atherosclerosis-associated inflammation.

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Oxidized LDL Disrupts Metabolism and Inhibits Macrophage Survival by Activating a miR-9/Drp1/Mitochondrial Fission Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/8848930 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Ting Xin ◽

Chengzhi Lu ◽

Jing Zhang ◽

Jiaxin Wen ◽

Shuangbin Yan ◽

...

Keyword(s):

Inflammatory Responses ◽

Cholesterol Metabolism ◽

Oxidized Ldl ◽

Mitochondrial Fission ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

The Novel ◽

Macrophage Viability

Mitochondrial dysfunction is associated with macrophage damage, but the role of mitochondrial fission in macrophage cholesterol metabolism is not fully understood. In this study, we explored the influences of miR-9 and mitochondrial fission on macrophage viability and cholesterol metabolism. Macrophages were incubated with oxidized low-density lipoprotein (ox-LDL) in vitro, after which mitochondrial fission, cell viability, and cholesterol metabolism were examined using qPCR, ELISAs, and immunofluorescence. ox-LDL treatment significantly increased Drp1-associated mitochondrial fission. Transfection of Drp1 siRNA significantly reduced cell death, attenuated oxidative stress, and inhibited inflammatory responses in ox-LDL-treated macrophages. Interestingly, inhibition of Drp1-related mitochondrial fission also improved cholesterol metabolism by balancing the transcription of cholesterol influx/efflux enzymes. We also found that miR-9 was downregulated in ox-LDL-treated macrophages, and administration of a miR-9 mimic decreased Drp1 transcription and mitochondrial fission, as well as its effects. These results indicate that signaling via the novel miR-9/Drp1/mitochondrial fission axis is a key determinant of macrophage viability and cholesterol metabolism.

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Oxidized LDL but not angiotensin II induces the interaction between LOX-1 and AT1 receptors

10.1101/2020.12.14.422633 ◽

2020 ◽

Author(s):

Li Lin ◽

Ning Zhou ◽

Le Kang ◽

Qi Wang ◽

Jian Wu ◽

...

Keyword(s):

Angiotensin Ii ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Direct Interaction ◽

Cardiomyocyte Hypertrophy ◽

Oxidized Low Density Lipoprotein ◽

Protein Activation

Oxidized low-density lipoprotein (Ox-LDL) can induce cardiac hypertrophy, but the mechanism is still unclear. Here we elucidate the role of angiotensin II (AngII) receptor (AT1-R) in Ox-LDL-induced cardiomycyte hypertrophy. Inhibition of Ox-LDL receptor LOX-1 and AT1-R rather than AngII abolished Ox-LDL-induced hypertrophic responses. Similar results were obtained from the heart of mice lacking endogenous Ang II and their cardiomyocytes. Ox-LDL but not AngII induced binding of LOX-1 to AT1-R, and the inhibition of LOX-1 or AT1-R rather than AngII abolished the association of these two receptors. Ox-LDL-induced ERKs phosphorylation in LOX-1 and AT1-R-overexpression cells and the binding of both receptors were suppressed by the mutants of LOX-1 (Lys266Ala/Lys267Ala) or AT1-R (Glu257Ala), however, the AT1-R mutant lacking Gq protein-coupling ability only abolished the ERKs phosphorylation. The phosphorylation of ERKs induced by Ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by Gq protein inhibitor but not by Jak2, Rac1 and RhoA inhibitors. Therefore, the direct interaction between LOX-1 and AT1-R and the downstream Gq protein activation are important mechanisms for Ox-LDL- but not AngII-induced cardiomyocyte hypertrophy

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Treatment of macrophages with oxidized low-density lipoprotein increases their intracellular glutathione content

Biochemical Journal ◽

10.1042/bj2780429 ◽

1991 ◽

Vol 278 (2) ◽

pp. 429-434 ◽

Cited By ~ 58

Author(s):

V M Darley-Usmar ◽

A Severn ◽

V J O'Leary ◽

M Rogers

Keyword(s):

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Human Monocyte ◽

Cell Types ◽

Oxidative Modification ◽

Glutathione Depletion ◽

Lipid Phase ◽

Low Density ◽

Oxidized Low Density Lipoprotein

Macrophages derived from the human monocyte cell line THP-1 or isolated from the peritoneum of C3H/HEJ mice were incubated with oxidized low-density lipoprotein (LDL) and the total glutathione content (oxidized plus reduced) was measured. An initial depletion of glutathione was followed by an increase, such that after a period of 24 h the glutathione content has approximately doubled. This response required the oxidation of the lipid phase of the LDL molecule, since both native LDL and acetylated LDL had little effect on glutathione levels. The response of the cells to oxidized LDL was dependent on the extent of oxidative modification of the protein. It was also found that 4-hydroxynonenal had a similar effect on THP-1 cells, and we suggest that this or other aldehydes present in oxidized LDL causes the induction of glutathione synthesis in response to an initial oxidative stress and consequent glutathione depletion. In addition, we found that both cell types possess transferases and peroxidases capable of detoxifying aldehydes and peroxides. However, treatment of cells with oxidized LDL or 4-hydroxynonenal for a period of 24 h had no effect on the activities of these enzymes.

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Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2018.0147 ◽

2018 ◽

Vol 374 (1765) ◽

pp. 20180147 ◽

Cited By ~ 10

Author(s):

Sasha A. Doodnauth ◽

Sergio Grinstein ◽

Michelle E. Maxson

Keyword(s):

Foam Cell ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Immune Surveillance ◽

Density Lipoprotein ◽

Unique Type ◽

Functional Roles ◽

Fluid Uptake ◽

Molecular Patterns

Macrophages respond to several stimuli by forming florid membrane ruffles that lead to fluid uptake by macropinocytosis. This type of induced macropinocytosis, executed by a variety of non-malignant and malignant cells, is initiated by transmembrane receptors and is involved in nutrient acquisition and mTOR signalling. However, macrophages also perform a unique type of constitutive ruffling and macropinocytosis that is dependent on the presence of extracellular calcium. Calcium-sensing receptors are responsible for this activity. This distinct form of macropinocytosis enables macrophages to continuously sample their microenvironment for antigenic molecules and for pathogen- and danger-associated molecular patterns, as part of their immune surveillance functions. Interestingly, even within the monocyte lineage, there are differences in macropinocytic ability that reflect the polarized functional roles of distinct macrophage subsets. This review discusses the shared and distinct features of both induced and constitutive macropinocytosis displayed by the macrophage lineage and their roles in physiology, immunity and pathophysiology. In particular, we analyse the role of macropinocytosis in the uptake of modified low-density lipoprotein (LDL) and its contribution to foam cell and atherosclerotic plaque formation. We propose a combined role of scavenger receptors and constitutive macropinocytosis in oxidized LDL uptake, a process we have termed ‘receptor-assisted macropinocytosis'. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

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Role of Lectin-Like Oxidized Low Density Lipoprotein-1 in Fetoplacental Vascular Dysfunction in Preeclampsia

BioMed Research International ◽

10.1155/2014/353616 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Felipe A. Zuniga ◽

Valeska Ormazabal ◽

Nicolas Gutierrez ◽

Valeria Aguilera ◽

Claudia Radojkovic ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Vascular Dysfunction ◽

Pathological Condition ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Fetal Loss ◽

Density Lipoprotein ◽

Placental Tissue

The bioavailability of nitric oxide (NO) represents a key marker in vascular health. A decrease in NO induces a pathological condition denominated endothelial dysfunction, syndrome observed in different pathologies, such as obesity, diabetes, kidney disease, cardiovascular disease, and preeclampsia (PE). PE is one of the major risks for maternal death and fetal loss. Recent studies suggest that the placenta of pregnant women with PE express high levels of lectin-like oxidized LDL receptor-1 (LOX-1), which induces endothelial dysfunction by increasing reactive oxygen species (ROS) and decreasing intracellular NO. Besides LOX-1 activation induces changes in migration and apoptosis of syncytiotrophoblast cells. However, the role of this receptor in placental tissue is still unknown. In this review we will describes the physiological roles of LOX-1 in normal placenta development and the potential involvement of this receptor in the pathophysiology of PE.

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Cellular immunity, low-density lipoprotein and atherosclerosis: Break of tolerance in the artery wall

Thrombosis and Haemostasis ◽

10.1160/th11-05-0321 ◽

2011 ◽

Vol 106 (11) ◽

pp. 779-786 ◽

Cited By ~ 70

Author(s):

Daniel Ketelhuth ◽

Göran Hansson

Keyword(s):

T Cells ◽

T Cell ◽

Cellular Immunity ◽

Inflammatory Responses ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Chronic Inflammatory Disease ◽

Research Field ◽

T Cell Subsets ◽

Low Density

SummaryAtherosclerosis is a chronic inflammatory disease. Atherosclerotic plaques contain abundant immune cells that can dictate and effect inflammatory responses. Among them, T cells are present during all stages of the disease suggesting that they are essential in the initiation as well as the progression of plaque. Experimental as well as clinical research has demonstrated different T cell subsets, i.e. CD4+ Th1, Th2, Th17, and Treg as well as CD8+ and NKT cells in the plaque. Moreover, candidate antigens inducing T cell responses have been identified. Knowledge about the pathological role of these cells in atherogenesis may lead to development of new therapies. This review provides an overview of the research field of cellular immunity in atherosclerosis. It emphasises the events and findings involving antigen specific T cells, in particular low-density lipoprotein-specific T cells.

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Abstract 189: The Role of Spleen Tyrosine Kinase, Syk, in CD36-Toll Like Receptor Cooperative Signaling in Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a189 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Tathagat Dutta Ray ◽

Bhama Ramkhelawon ◽

Kathryn J Moore

Keyword(s):

Tyrosine Kinase ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Oxidized Ldl ◽

Density Lipoprotein ◽

Sh2 Domain ◽

Sterile Inflammation ◽

Toll Like Receptor ◽

Spleen Tyrosine Kinase

Atherosclerosis is characterized by chronic sterile inflammation of the artery wall in which cells of the monocyte lineage accumulate in response to the deposition of low density lipoprotein (LDL). We previously established that recognition of oxidized LDL (oxLDL) by CD36 triggers assembly of a novel Toll-like receptor heterodimer composed of TLR4 and TLR6. Here we set out to understand the molecular mechanisms of CD36/TLR4/TLR6 activation and establish how it triggers downstream signals that lead to the expression of the pro-inflammatory mediators that have been directly implicated in the deleterious effects of oxLDL and atherosclerosis progression. By confocal microscopy we demonstrate that oxLDL induces CD36, TLR4 and TLR6 co-localization in intracellular compartments, but not on the cell surface of macrophages. Notably, inhibition of oxLDL endocytosis (with Dynasore) or lysosomal maturation (with Bafilomycin A or NH4Cl) blocks CD36-TLR4-TLR6 complex formation and oxLDL-induced cytokine responses in macrophages. These data indicate that both ligand internalization and lysosomal acidification are required for assembly of a functional CD36/TLR4/TLR6 signaling complex. Notably, CD36 contains a hemi-ITIM motif in the C-terminus that is reported to interact with the spleen tyrosine kinase Syk through its SH2 domain. As Syk has recently been implicated in the trafficking of CD14 and TLR4 to the endosome in response to LPS, we investigated the role of this kinase in CD36/TLR4/TLR6 signaling. We find that Syk is required for CD36 internalization and TLR4/TLR6 heterodimerization. Using a pharmacological inhibitor, we show that inhibition of Syk activity blocks oxLDL-induced TLR4-TLR6 co-precipitation and abrogates macrophage expression of both MyD88- (IL-1b, CXCL1) and TRIF-dependent (CCL5) cytokines/chemokines. Together, our data are consistent with a key role for Syk in the trafficking of CD36 and oxLDL to the lysosome, where it coordinates the assembly of a functional TLR4-TLR6 heterodimer to initiate signaling. This model highlights the importance of CD36 as a co-receptor that orchestrates TLR4-TLR6 trafficking and assembly to initiate the detrimental inflammatory responses that promote the progression of atherosclerosis.

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Low density lipoprotein increases amyloid precursor protein processing to amyloidogenic pathway in differentiated SH-SY5Y cells

Biologia ◽

10.1515/biolog-2017-0024 ◽

2017 ◽

Vol 72 (2) ◽

Author(s):

Panit Yamchuen ◽

Rattima Jeenapongsa ◽

Sutisa Nudmamud-Thanoi ◽

Nanteetip Limpeanchob

Keyword(s):

Amyloid Precursor Protein ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Neuroblastoma Cells ◽

Density Lipoprotein ◽

Precursor Protein ◽

Amyloid Precursor Protein Processing ◽

Low Density ◽

App Processing

AbstractHypercholesterolemia has been considered as a risk factor for Alzheimer’s disease (AD). In addition to low density lipoprotein (LDL), oxidized LDL plays some roles in AD pathology. Neurodegenerative effect of oxidized LDL was supported by the increased oxidative stress in neurons. To further investigate the role of oxidized LDL, the present study aimed to test its effect on amyloid precursor protein (APP) processing. The release of soluble APP (sAPP) was evaluated in differentiated SH-SY5Y neuroblastoma cells exposed to native (non-oxidized) or oxidized human LDL including mildly and fully oxidized LDL (mox- and fox-LDL). Non-amyloidogenic and amyloidogenic pathways were investigated using specific antibody against sAPP

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Lipoprotein lipase stimulates the binding and uptake of moderately oxidized low-density lipoprotein by J774 macrophages

Biochemical Journal ◽

10.1042/bj3140563 ◽

1996 ◽

Vol 314 (2) ◽

pp. 563-568 ◽

Cited By ~ 35

Author(s):

Wendy L. HENDRIKS ◽

Hans van der BOOM ◽

Leonie C. van VARK ◽

Louis M. HAVEKES

Keyword(s):

Lipoprotein Lipase ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Heparan Sulphate ◽

Density Lipoprotein ◽

Cell Types ◽

Low Density ◽

Dependent Manner ◽

Dose Dependent

Lipoprotein lipase (LPL) stimulates the uptake of low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) in different cell types, including macrophages, through bridging of LPL between lipoproteins and extracellular heparan sulphate proteoglycans (HSPG). Because macrophages produce LPL and because modified lipoproteins are present in the arterial wall in vivo, we wondered whether LPL also enhances the uptake of oxidized LDL by J774 macrophages. LDL samples with different degrees of oxidation, as evaluated by relative electrophoretic mobility (REM) as compared with native LDL are used, as well as native and acetylated LDL. Addition of 5 μg/ml LPL to the J774 cell culture medium stimulated the binding of both native LDL and moderately oxidized LDL (REM < 3.5) 50–100-fold, and their uptake was stimulated approx. 20-fold. The LPL-mediated binding of native LDL and moderately oxidized LDL was dose-dependent. Preincubation of the cells with heparinase (2.4 units/ml) inhibited the stimulatory effect of LPL, indicating that this LPL-mediated stimulation was due to bridging between the lipoproteins and HSPG. The binding to J774 macrophages of severely oxidized LDL (REM = 4.3) was stimulated less than 3-fold by LPL, whereas its uptake was not stimulated significantly. The binding and uptake of acetylated LDL (AcLDL) were not stimulated by LPL, although the LPL-molecule itself does bind to AcLDL. Measurements of the cellular lipid content showed that addition of LPL also stimulated the accumulation in the cells of cholesteryl ester derived from both native LDL and moderately oxidized LDL in a dose-dependent manner. We conclude that our results present experimental evidence for the hypothesis that LPL serves as an atherogenic component in the vessel wall.

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Recognition of Oxidized Lipids by Macrophages and Its Role in Atherosclerosis Development

Biomedicines ◽

10.3390/biomedicines9080915 ◽

2021 ◽

Vol 9 (8) ◽

pp. 915

Author(s):

Nataliya V. Mushenkova ◽

Evgeny E. Bezsonov ◽

Varvara A. Orekhova ◽

Tatyana V. Popkova ◽

Antonina V. Starodubova ◽

...

Keyword(s):

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Formation Mechanisms ◽

Therapeutic Approaches ◽

Macrophage Response ◽

New Therapeutic Approaches ◽

Metabolic Imbalance ◽

Atherosclerosis Development

Atherosclerosis is a multifactorial chronic disease that has a prominent inflammatory component. Currently, atherosclerosis is regarded as an active autoimmune process that involves both innate and adaptive immune pathways. One of the drivers of this process is the presence of modified low-density lipoprotein (LDL). For instance, lipoprotein oxidation leads to the formation of oxidation-specific epitopes (OSE) that can be recognized by the immune cells. Macrophage response to OSEs is recognized as a key trigger for initiation and a stimulator of progression of the inflammatory process in the arteries. At the same time, the role of oxidized LDL components is not limited to pro-inflammatory stimulation, but includes immunoregulatory effects that can have protective functions. It is, therefore, important to better understand the complexity of oxidized LDL effects in atherosclerosis in order to develop new therapeutic approaches to correct the inflammatory and metabolic imbalance associated with this disorder. In this review, we discuss the process of oxidized LDL formation, mechanisms of OSE recognition by macrophages and the role of these processes in atherosclerosis.

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