scholarly journals Candida albicans Induces Foaming and Inflammation in Macrophages through FABP4: Its Implication for Atherosclerosis

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1567
Author(s):  
Mohammed Haider ◽  
Fatema Al-Rashed ◽  
Zahraa Albaqsumi ◽  
Khaled Alobaid ◽  
Rawan Alqabandi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Inflammatory Markers ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Low Grade ◽  
Macrophage Phenotype ◽  
Degenerative Disorder ◽  
Interfering Rna ◽  
Low Grade Inflammation

Atherosclerosis is a chronic degenerative disorder characterized by lipid-dense plaques and low-grade inflammation affecting arterial walls. Foamy macrophages are important in the formation of atherosclerotic plaques and the induction of low-grade inflammation. The presence of lipid-laden macrophages has occurred in infections caused by opportunistic pathogens. Candida albicans is the major cause of candidiasis in immunocompromised patients, including those with diabetes mellitus. However, the role played by C. albicans in macrophage foaming and the associated inflammation is poorly understood. We investigated whether C. albicans induces foaming along with inflammation in macrophages and, if so, by which mechanism(s). We incubated THP-1 macrophages with heat-killed C. albicans (HKCA). HKCA-induced lipid accumulation in macrophages along with increased expression of inflammatory markers, including CD11b and CD11c or expression and secretion of IL-1β. HKCA also increased the expression of PPARγ, CD36, and FABP4 in macrophages. Mechanistically, we found that the foamy and inflammatory macrophage phenotype induced by HKCA requires FABP4 because disruption of FABP4 in macrophages either by chemical inhibitor BMS309404 or small interfering RNA (siRNA) abrogated foam cell formation and expression of inflammatory markers CD11b, CD11c, and IL-1β. Furthermore, HKCA-treated macrophages displayed high expression and secretion of MMP-9. Inhibition of FABP4 resulted in suppression of HCKA-induced MMP-9 production. Overall, our results demonstrate that C. albicans induces foam cell formation, inflammation, and MMP-9 expression in macrophages via the upregulation of FABP4, which may constitute a novel therapeutic target for treating C. albicans-induced atherosclerosis.

Soluble CD40 Ligand Promotes Macrophage Foam Cell Formation in the Etiology of Atherosclerosis

Cardiology ◽  
2015 ◽  
Vol 131 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Ming Yuan ◽  
Hongjie Fu ◽  
Lifen Ren ◽  
Haichang Wang ◽  
Wenyi Guo
Keyword(s):  
Small Interfering Rna ◽  
Foam Cell ◽  
Cell Formation ◽  
Cd40 Ligand ◽  
Foam Cell Formation ◽  
Lipid Deposition ◽  
Soluble Cd40 Ligand ◽  
Important Indicator ◽  
Interfering Rna

Objective: High levels of soluble CD40 ligand (sCD40L) in the circulation have been suggested as an important indicator of cardiovascular diseases such as atherosclerosis and acute coronary syndromes. In the present study, we explored the role of sCD40L in the formation of foam cells. Methods: Lipid deposition and foam cell formation was measured by high-performance liquid chromatography and Nile Red staining, respectively. Gene expressions were detected by quantitative real-time PCR and Western blot analysis. The interaction between CD40 and sCD40L were blocked by CD40 small interfering RNA or anti-CD40 antibody. Results: sCD40L significantly increased lipid deposition and foam cell formation associated with upregulation of scavenger receptor type A and CD36. Additionally, sCD40L increased adipocyte enhancer-binding protein 1 and cholesterol efflux, and activated NF-κB in macrophages. sCD40L promoted foam cell formation via CD40 ligation and disruption of the ligation between CD40 and CD40L either by small interfering RNA or by a blocking anti-CD40 antibody apparently inhibiting foam cell formation in response to sCD40L. Conclusion: Our data suggests a novel insight into the role of sCD40L in foam cell formation during atherosclerosis, which further confirms the importance of sCD40L in atherosclerosis and as a target for the treatment of this disease.

scholarly journals eIF6 Promotes Inflammatory Macrophage Phenotype, Foam Cell Formation and Atherosclerosise

2021 ◽  
Author(s):  
Junnian Zheng ◽  
Renjin Chen ◽  
Xuemei Xian ◽  
xiaoqiang Zhan ◽  
Jiajia Chang ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Western Diet ◽  
Initiation Factor ◽  
Immunofluorescent Staining ◽  
Foam Cell Formation ◽  
Macrophage Phenotype ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage ◽  
Novel Therapeutic

Abstract Background：Atherosclerosis is a chronic inflammatory disease, caused by accumulation of lipid-laden and inflammatory macrophages in the artery wall. Understanding its molecular mechanisms and developing novel therapeutic targets to promote atherosclerotic regression is an important clinical goal.Methods : ApoE-/- and eIF6+/-/ApoE-/- mice were fed Western diet (WD) for 16 weeks. Molecular biology technology were performed to analyze the differences between them.Results: The mechanism by which Eukaryotic initiation factor 6 (eIF6) affects macrophages and atherosclerosis remains to be elucidated. Western blotting and real-time polymerase chain reaction (PCR ) analysis indicated significantly higher expression levels of eIF6 than those in the control in RAW264.7 cells induced by Lipopolysaccharide (LPS) and Interleukin-4 (IL4). We constructed eIF6+/-/ApoE-/- mice, the hematoxylin (HE) and Oil Red O staining analysis indicated that these mice showed a significant decrease in atherosclerotic lesion formation increased anti-inflammatory cell content in aortas, and reduced necrotic core content compared with ApoE-/- mice on a western diet for 16 weeks. eIF6 deficiency suppressed foam cell formation and promoted the anti-inflammatory macrophage phenotype in primary macrophages. More anti-inflammatory populations were observed in blood and atherosclerotic aortas of eIF6+/- ApoE-/- mice by flow cytometry. Immunofluorescent staining analysis obtained the same results.Conclusions: eIF6 deficiency protects against atherosclerosis by promoting the anti-inflammatory macrophage phenotype and reducing macrophage uptake of low-density lipoprotein (LDL), indicating that new insight into eIF6 may reveal a potential novel therapeutic target for the resolution of inflammation in atherosclerosis.

Postprandial inflammation and endothelial dysfuction

2007 ◽  
Vol 35 (3) ◽  
pp. 466-469 ◽  
Author(s):  
A. Alipour ◽  
J.W.F. Elte ◽  
H.C.T. van Zaanen ◽  
A.P. Rietveld ◽  
M. Castro Cabezas
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Inflammatory Cells ◽  
Chronic Inflammatory Disease ◽  
Western World ◽  
Foam Cell Formation ◽  
Central Component ◽  
Low Grade ◽  
Postprandial Lipaemia ◽  
The Metabolic Syndrome

Postprandial hyperlipidaemia is a common metabolic disturbance in atherosclerosis. During the postprandial phase, chylomicrons and their remnants can penetrate the intact endothelium and cause foam cell formation. These particles are highly atherogenic after modification. People in the Western world are non-fasting for most of the day, which consequently leads to a continuous challenge of the endothelium by atherogenic lipoproteins and their remnants. Furthermore, atherosclerosis is considered a low-grade chronic inflammatory disease. Many studies have shown that the process of atherogenesis in part starts with the interaction between the activated leucocytes and activated endothelium. Postprandial lipoproteins can activate leucocytes in the blood and up-regulate the expression of leucocyte adhesion molecules on the endothelium, facilitating adhesion and migration of inflammatory cells into the subendothelial space. Another inflammatory process associated with postprandial lipaemia is the activation of the complement system. Its central component C3 has been associated with obesity, coronary sclerosis, the metabolic syndrome and fasting and postprandial TAGs (triacylglycerols). Moreover, chylomicrons are the strongest stimulators of adipocyte C3 production via activation of the alternative complement cascade. A postprandial C3 increment has been shown in healthy subjects and in patients with CAD (coronary artery disease) and with FCHL (familial combined hyperlipidaemia). Postprandial lipaemia has been related to TAG and free fatty acid metabolism. All of these mechanisms provide an alternative explanation for the atherogenicity of the postprandial period.

scholarly journals Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

2019 ◽  
Vol 5 (10) ◽  
pp. eaax9183 ◽  
Author(s):  
Jessica M. Johnston ◽  
Adrienn Angyal ◽  
Robert C. Bauer ◽  
Stephen Hamby ◽  
S. Kim Suvarna ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Strongly Correlated ◽  
Macrophage Phenotype ◽  
Chd Risk

Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

scholarly journals Macrophage Long Non-Coding RNAs in Pathogenesis of Cardiovascular Disease

2020 ◽  
Vol 6 (3) ◽  
pp. 28
Author(s):  
Marcin Wysoczynski ◽  
Jae Kim ◽  
Joseph B. Moore ◽  
Shizuka Uchida
Keyword(s):  
Cardiovascular Disease ◽  
Cell Fate ◽  
Foam Cell ◽  
Current Knowledge ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Macrophage Phenotype ◽  
Macrophage Function ◽  
Cell Fate Decisions ◽  
Non Coding Rnas

Chronic inflammation is inextricably linked to cardiovascular disease (CVD). Macrophages themselves play important roles in atherosclerosis, as well as acute and chronic heart failure. Although the role of macrophages in CVD pathophysiology is well-recognized, little is known regarding the precise mechanisms influencing their function in these contexts. Long non-coding RNAs (lncRNAs) have emerged as significant regulators of macrophage function; as such, there is rising interest in understanding how these nucleic acids influence macrophage signaling, cell fate decisions, and activity in health and disease. In this review, we summarize current knowledge regarding lncRNAs in directing various aspects of macrophage function in CVD. These include foam cell formation, Toll-like receptor (TLR) and NF-kβ signaling, and macrophage phenotype switching. This review will provide a comprehensive understanding concerning previous, ongoing, and future studies of lncRNAs in macrophage functions and their importance in CVD.

scholarly journals Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

2019 ◽  
Author(s):  
Jessica M Johnston ◽  
Adrienn Angyal ◽  
Robert C Bauer ◽  
Stephen Hamby ◽  
S Kim Suvarna ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Strongly Correlated ◽  
Macrophage Phenotype ◽  
Chd Risk

AbstractMacrophages drive atherosclerotic plaque progression and rupture, hence attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

Abstract 239: Deficiency of Macrophage Epsins Impedes Atherosclerosis by Inhibiting LRP-1 Internalization and Degradation

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Megan L Brophy ◽  
Ashiqur Rahman ◽  
Yunzhou Dong ◽  
Hao Wu ◽  
Kandice L Tessneer ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Gene Profiling ◽  
Foam Cell Formation ◽  
Macrophage Phenotype ◽  
M1 Macrophage ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage

Background: Atherosclerosis is caused by the chronic activation of the vascular endothelium and immune and inflammatory cell infiltration of the vascular wall, leading to enhanced inflammation and lipid accumulation. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Epsins are a family of ubiquitin-binding endocytic adaptors. However, their role in vascular inflammation is poorly understood. Our goal is to define the novel role of epsins in regulating atherogenesis. Methods and Results: We engineered mice with specific deletion of epsins in myeloid cells (MΦ-DKO). Strikingly, MΦ-DKO mice on an ApoE-/- background fed western diet exhibited reduced atherosclerotic lesion and foam cell accumulation, and diminished recruitment of immune or inflammatory cells to aortas by FACS analysis. In primary macrophages, epsin deficiency impaired foam cell formation by Oil Red O staining, and suppressed the pro-inflammatory M1 macrophage phenotype but increased the anti-inflammatory macrophage phenotype by gene profiling. Epsin deficiency did not alter levels of LDL scavenger receptors, or reverse cholesterol transport proteins, but did increase total and surface levels of LRP-1, a protein with anti-inflammatory and anti-atherosclerotic properties. Mechanistically, Epsin interacts with LRP-1 via epsin’s UIM domain. LPS treatment increased LRP-1 ubiquitination and subsequent binding to epsin, suggesting that epsin promotes the ubiquitin-dependent internalization and degradation of LRP-1. Accordingly, macrophages isolated from MΦ-DKO mice on LRP-1 heterozygous background restored the pro-inflammatory phenotype. Conclusions: Epsins promote atherogenesis by facilitating pro-inflammatory macrophage recruitment and potentiating foam cell formation by downregulating LRP-1 implicating that targeting the epsin-LRP-1 interaction may serve as a novel therapeutic strategy to treat atheromas.

Abstract 94: Deficiency of Epsins in Macrophages Ameliorates Atherosclerosis by Attenuating Inflammation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Megan L Brophy ◽  
Yunzhou Dong ◽  
Hao Wu ◽  
Kai Song ◽  
Ashiqur Rahman ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Cell ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Macrophage Phenotype ◽  
M1 Macrophage ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage

Background: Atherosclerosis is caused by the immune and inflammatory cell infiltration of the vascular wall, leading to enhanced inflammation and lipid accumulation. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Our recently studies demonstrate that endothelial epsins, a family of ubiquitin-binding endocytic adaptors are critical regulators of atherosclerosis. However, whether epsins in macrophages play a role in regulating vascular inflammation is unknown. We hypothesize that epsins in macrophages promote inflammation to facilitate atherogenesis. Methods and Results: We engineered myeloid cell-specific epsins double knockout mice (MΦ-DKO) on an ApoE-/- background fed western diet. Strikingly, these mice exhibited reduced atherosclerotic lesion formation, diminished immune and inflammatory cell recruitment to aortas and reduced cleaved caspase 3 staining but increased α-SMA staining within aortic root sections. Epsin deficiency hindered foam cell formation, suppressed the pro-inflammatory M1 macrophage phenotype but increased the anti-inflammatory macrophage phenotype, and enhanced efferocytosis in primary macrophages. Mechanistically, we show that epsin loss specifically increases total and surface levels of LRP-1, a protein with anti-inflammatory properties without altering levels of LDL scavenger receptors. We further show that epsin and LRP-1 interact via epsin’s UIM domain. Oxidized LDL treatment increased LRP-1 ubiquitination and subsequent binding to epsin while mutation of cytoplasmic lysine residues attenuated LRP-1 ubiquitination, suggesting that epsin promotes the ubiquitin-dependent internalization and degradation of LRP-1. Importantly, MΦ-DKO/ApoE null mice on LRP-1 heterozygous background restored atherosclerosis, suggesting that epsin-mediated LRP-1 downregulation in macrophages plays a pivotal role in propelling atherogenesis. Conclusions: Macrophage epsins promote atherogenesis, in part, by facilitating pro-inflammatory macrophage recruitment and potentiating foam cell formation by downregulating LRP-1, implicating that targeting epsin in macrophages may serve as a novel therapeutic strategy to treat atheroma.

scholarly journals PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPARγ Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Wen-Lin Cheng ◽  
Quan Zhang ◽  
Bo Li ◽  
Jian-Lei Cao ◽  
Lin Jiao ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Foam Cell ◽  
Macrophage Polarization ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Loss Of Function ◽  
M1 Macrophage ◽  
Pparγ Expression

Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

EM of human atherosclerosis: Aortic fatty streaks with transitional lesion features

1992 ◽  
Vol 50 (1) ◽  
pp. 622-623
Author(s):  
K. Florian Klemp ◽  
J.R. Guyton
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Processing Technique ◽  
Foam Cell Formation ◽  
Tissue Preparation ◽  
Electron Microscopic ◽  
Extracellular Lipid ◽  
Electron Microscopic Cytochemistry ◽  
Human Atherosclerosis ◽  
Clinically Significant

The earliest distinctive lesions in human atherosclerosis are fatty streaks (FS), characterized initially by lipid-laden foam cell formation. Fibrous plaques (FP), the clinically significant lesions, differ from FS in several respects. In addition to foam cells, the FP also exhibit fibromuscular proliferation and a necrotic core region rich in extracellular lipid. The possible transition of FS into mature FP has long been debated, however. A subset of FS described by Katz etal., was intermediate in lipid composition between ordinary FS and FP. We investigated this hypothesis by electron microscopic cytochemistry by employing a tissue processing technique previously described by our laboratory. Osmium-tannic acid-paraphenylenediamine (OTAP) tissue preparation enabled ultrastructural analysis of lipid deposits to discern features characteristic of mature fibrous plaques.

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