scholarly journals Lupeol Counteracts the Proinflammatory Signalling Triggered in Macrophages by 7-Keto-Cholesterol: New Perspectives in the Therapy of Atherosclerosis

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Sarmistha Saha ◽  
Elisabetta Profumo ◽  
Anna Rita Togna ◽  
Rachele Riganò ◽  
Luciano Saso ◽  
...  
Keyword(s):  
Foam Cell ◽  
Macrophage Polarization ◽  
Cholesterol Oxidation ◽  
Foam Cell Formation ◽  
Immunomodulatory Activity ◽  
Ros Production ◽  
M1 Macrophages ◽  
Functional Changes ◽  
Hla Dr ◽  
Anti Inflammatory

Macrophage activation and polarization play a central role in atherosclerotic plaque fate. The M1/M2 activation phenotypes represent two profiles of the macrophage polarization state. During atherosclerosis regression or stabilization, macrophages switch from M1 proinflammatory phenotype to M2 anti-inflammatory reparative one. Here, we investigated whether the natural compound lupeol, a pentacyclic triterpene, induces phenotypical and functional changes in human M1 macrophages and counteracts the proinflammatory signalling triggered by 7-keto-cholesterol (7KC), a major product of oxidative stress-mediated cholesterol oxidation. Flow cytometric and immunochemical analysis showed that the treatment with lupeol of M1 monocyte-derived macrophages M(IFN-γ/LPS) specifically stimulated these cells to upregulate the expression of the anti-inflammatory cytokines interleukin- (IL-)10 and TGF-β, and of the scavenger receptor CD36, whereas downregulated the proinflammatory cytokine IL-12 and the M1 activation marker HLA-DR. Pretreatment of macrophages with lupeol prevented the release of IL-12, IL-1β, and the upregulation of HLA-DR expression triggered by 7KC and increased the IL-10 production and CD36 expression. This treatment also prevented the impairment of endocytosis triggered by 7KC and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M1-polarized THP-1 macrophages, whereas showed an additive effect in reactive oxygen species (ROS) production. Western blotting analysis of autophagy markers LC3-I/II and p62-SQSTM1 in M1-polarized THP-1 macrophages demonstrated that lupeol activated autophagy as indicated by increased LC3-II levels, and by marked inhibition of p62. These findings indicate that lupeol has a cytoprotective effect on 7KC-proinflammatory signalling by efficiently switching the macrophage polarization toward an anti-inflammatory phenotype, probably through the activation of the autophagy pathway by increasing ROS production, the reduction of cellular lipid accumulation, and an overall reduction of proinflammatory phenotype. Thus, our data demonstrating an anti-inflammatory and immunomodulatory activity of lupeol in human M1 macrophages suggest its usefulness as an adjunctive drug in the therapy of atherosclerosis.

Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation

2011 ◽  
Vol 106 (11) ◽  
pp. 763-771 ◽  
Author(s):  
Ine Wolfs ◽  
Marjo Donners ◽  
Menno de Winther
Keyword(s):  
Inflammatory Cell ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
M1 Macrophages ◽  
Macrophage Polarisation ◽  
Atherosclerotic Lesions ◽  
Differentiation Factors

SummaryThe phenotype of macrophages in atherosclerotic lesions can vary dramatically, from a large lipid laden foam cell to a small inflammatory cell. Classically, the concept of macrophage heterogeneity discriminates between two extremes called either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Polarisation of plaque macrophages is predominantly determined by the local micro-environment present in the atherosclerotic lesion and is rather more complex than typically described by the M1/M2 paradigm. In this review we will discuss the role of various polarising factors in regulating the phenotypical state of plaque macrophages. We will focus on two main levels of phenotype regulation, one determined by differentiation factors produced in the lesion and the other determined by T-cell-derived polarising cytokines. With foam cell formation being a key characteristic of macrophages during atherosclerosis initiation and progression, these polarisation factors will also be linked to lipid handling of macrophages.

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.

scholarly journals TET1 Knockdown Inhibits Porphyromonas gingivalis LPS/IFN-γ-Induced M1 Macrophage Polarization through the NF-κB Pathway in THP-1 Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 2023 ◽  
Author(s):  
Huang ◽  
Tian ◽  
Li ◽  
Xu
Keyword(s):  
Porphyromonas Gingivalis ◽  
Periodontal Diseases ◽  
Macrophage Polarization ◽  
Control Group ◽  
M1 Macrophages ◽  
Expression Levels ◽  
Hla Dr ◽  
M1 Macrophage ◽  
Significant Difference ◽  
Ifn Γ

Tet-eleven translocation 1 (TET1) is a dioxygenase that plays an important role in decreasing the abundance of DNA methylation and changing the expression levels of specific genes related to inflammation. Porphyromonas gingivalis (Pg.) lipopolysaccharide (LPS) can induce periodontal diseases that present with severe bone loss and collagen fiber destruction accompanied by a high number of M1 macrophages. M1-polarized macrophages are pivotal immune cells that promote the progression of the periodontal inflammatory response, but the function of TET1 during M1 macrophage activation is still unknown. Our results showed that the mRNA and protein expression levels of TET1 decreased in THP-1 cells during M1 macrophage differentiation. TET1 knockdown resulted in a significant decrease in the production of proinflammatory markers such as IL-6, TNF-α, CCL2, and HLA-DR in Pg. LPS/IFN-γ- and Escherichia coli (E. coli) LPS/IFN-γ-induced M1 macrophages. Mechanistically, TET1 knockdown downregulated the activity of the NF-κB signaling pathway. After treatment with the NF-κB inhibitor BAY 11-7082, M1 marker expression showed no significant difference between the TET1 knockdown group and the control group. Taken together, these results suggest that TET1 depletion inhibited Pg. LPS/IFN-γ-induced M1 macrophage polarization through the NF-κB pathway in THP-1 cells.

scholarly journals Role of adipokine zinc-α2-glycoprotein in coronary heart disease

2019 ◽  
Vol 317 (6) ◽  
pp. E1055-E1062
Author(s):  
Dandan Huang ◽  
Xiaoxiang Mao ◽  
Jiangtong Peng ◽  
Min Cheng ◽  
Tao Bai ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Atherosclerotic Plaques ◽  
293 Cells ◽  
Anti Inflammatory

Zinc-α2-glycoprotein (AZGP1) is a newly identified adipokine that is associated with lipid metabolism and vascular fibrosis. Although adipokines contribute to lipid dysfunction and its related diseases, including stroke and coronary heart disease (CHD), the role of AZGP1 remains unclear. In this study, the role of AZGP1 in atherosclerosis and CHD was investigated. Serum AZGP1 levels from control ( n = 84) and CHD ( n = 91) patients were examined by ELISA and its relationship with various clinical parameters was analyzed. Immunohistochemistry and immunofluorescence were used to detect the expression of AZGP1 and its receptor in coronary atherosclerotic arteries. THP-1 and human embryonic kidney 293 cells were used to verify its anti-inflammatory role in atherosclerosis. Serum AZGP1 levels in CHD patients were lower than controls ( P < 0.01) and independently associated with CHD prevalence ( P = 0.021). AZGP1 levels also inversely correlated with the Gensini score. Immunohistochemistry and immunofluorescence showed that AZGP1 and its receptor β3-adrenoceptor (β3-AR) colocalized in lipid-rich areas of atherosclerotic plaques, particularly around macrophages. In vitro, AZGP1 had no effect on foam cell formation but showed anti-inflammatory effects through its regulation of JNK/AP-1 signaling. In summary, AZGP1 is an anti-inflammatory agent that can be targeted for CHD treatment.

scholarly journals Anti-inflammatory, analgesic, and immunostimulatory effects of Luehea divaricata Mart. & Zucc. (Malvaceae) bark

2014 ◽  
Vol 50 (3) ◽  
pp. 599-610 ◽  
Author(s):  
Roseane Leandra da Rosa ◽  
Geisson Marcos Nardi ◽  
Adriana Graziele de Farias Januário ◽  
Renata Boçois ◽  
Katiane Paula Bagatini ◽  
...  
Keyword(s):  
Peritoneal Macrophages ◽  
Neutral Red ◽  
Biological Properties ◽  
Immunomodulatory Activity ◽  
Ros Production ◽  
Paw Edema ◽  
Phagocytic Capacity ◽  
Macrophage Activity ◽  
Analgesic Effects ◽  
Anti Inflammatory

Luehea divaricata (Malvaceae) is a plant widely used for treatment of various inflammatory and infectious conditions; however few reports discuss its biological properties. The aim of this study was to evaluate the anti-inflammatory and analgesic effects as well as the macrophage activity in mice treated with the hydroalcoholic crude extract of L. divaricata(CLD). Thin layer chromatography revealed presence of epicathequin, stigmasterol, lupeol and α,β-amyrin in the extract. To evaluate the anti-inflammatory and analgesic activities, animals were subjected to paw edema induced by carrageenan test, writhing, formalin and capsaicin tests. Immunomodulatory activity was evaluated by adhesion and phagocytic capacity, lysosomal volume, and reactive oxygen species (ROS) production by peritoneal macrophages, after daily treatment with CLD for 15 days. CLD promoted reduction in paw edema (36.8% and 50.2%; p<0.05 at doses of 100 and 300 mg/kg, respectively), inhibited writhing behavior at the higher dose (64.4%, p<0.05), reduced formalin reactivity (81.2% and 91.6% at doses of 100 and 300 mg/kg, respectively, p<0.05), and reduced capsaicin reactivity by 63.9% (300 mg/kg). CLD (200 mg• kg-1• day-1) increased phagocytosis capacity of macrophages (~3 fold, p<0.05), neutral red uptake (~50%, p<0.001), and ROS production (~90%, p<0.001). These data suggest that CLD possesses anti-inflammatory, analgesic and immunostimulatory properties.

PO9-210 CHOLESTEROL OXIDATION PRODUCTS INDUCE FOAM CELL FORMATION THROUGH CD36 OVEREXPRESSION

2007 ◽  
Vol 8 (1) ◽  
pp. 69
Author(s):  
G. Leonarduzzi ◽  
P. Gamba ◽  
S. Gargiulo ◽  
B. Sottero ◽  
G. Perrelli ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Oxidation Products ◽  
Cholesterol Oxidation ◽  
Foam Cell Formation ◽  
Cholesterol Oxidation Products

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 378: Macrophage ß3 Integrin is an Important Player in Inflammation and Cellular Plasticity

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Cristina A Wolf ◽  
Izabela Bobak ◽  
Xinming Su ◽  
Ellen Damm ◽  
Katherine N Weilbaecher ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Cellular Response ◽  
Foam Cell ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Cellular Plasticity ◽  
Β3 Integrin ◽  
Anti Inflammatory

Communication between cells and the surrounding environment is a crucial mechanism for survival. Integrins are membrane-bound molecules that are involved in signaling between the cells and the extracellular matrix, thereby influencing cytoskeletal stability and intracellular signaling. β3 integrin and its binding partner αv form the αvβ3 heterodimer that is expressed in various cells. We and others have described the consequences of its absence in inflammation, atherosclerosis and cancer in vivo. However, the distinct role of this integrin as a signaling molecule and the consequences of its absence for macrophage structure remain mostly elusive. Our aim is to further characterize the phenotype of β3-deficient (β3-/-) bone marrow-derived macrophages (BMDM) under stimulatory conditions (LPS and LDLs) compared to control cells in vitro. qPCR, WB, ELISA, migration, proliferation assays were used to investigate β3-/- BMDM and controls (wt BMDM and Raw 264.7). LPS was described to be not only pro- but also anti-inflammatory in a time-dependent manner. We show that LPS stimulation leads to high expression of pro-inflammatory cytokines (IL-1β and TNFα) shortly after treatment, while expression of anti-inflammatory cytokine (IL-10) arises at a later stage (12h post stimulation). Interestingly, β3-/- BMDM express more IL-1β than controls. IL-10 expression appears much earlier in β3-/- BMDM (6h post stimulation) but is reduced after 12h, indicating a faster and higher cellular response in the absence of the β3 integrin. OxLDL, the leading cause to foam cell formation, stimulates the expression of IL-1β in controls and β3-/- BMDM with the latter expressing significantly less of this cytokine indicating that lack of β3 causes differential cellular responses after LPS and oxLDL stimulation. Other LDL forms tested (nLDL, acLDL, cLDL) did not have any effect on IL-1β expression. In addition, we identified a higher proliferation rate in the β3-/- BMDM when cultured with M-CSF and a migration deficit in response to LPS, M-CSF and VEGF. Taken together, our results show that macrophage β3 deficiency causes differential cellular plasticity depending on the stimulus, with functional consequences that could be essential in inflammation and atherosclerosis.

Abstract 397: Aldehyde-Modified Hdl Has CD36-dependent Pro-Atherogenic Effects in Macrophages

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Rebecca L Holme ◽  
Alexandra C Chadwick ◽  
Yiliang Chen ◽  
Roy L Silverstein ◽  
Daisy Sahoo
Keyword(s):  
Cardiovascular Disease ◽  
Foam Cell ◽  
Cell Formation ◽  
Peritoneal Macrophages ◽  
Oxidative Modification ◽  
High Density Lipoproteins ◽  
Foam Cell Formation ◽  
Functional Changes ◽  
Hdl Function ◽  
Reactive Aldehydes

The role of high density lipoproteins (HDL) in protecting against cardiovascular disease is compromised when HDL undergoes modification during conditions of oxidative stress; however, the mechanisms underlying these changes in HDL function are not well defined. Reactive aldehydes such as acrolein (a major component in cigarette smoke) or major products of lipid peroxidation such as 4-hydroxynonenal (HNE) or malondialdehyde (MDA) are known to oxidize HDL in cardiovascular disease. To test the hypothesis that modification of HDL with aldehydes impairs HDL’s athero-protective functions in macrophages, we first measured the ability of modified HDL to protect against foam cell formation. Cholesterol-loaded peritoneal macrophages isolated from wild-type C57Bl/J mice were incubated with native HDL, acrolein-modified HDL (acro-HDL), HNE-modified HDL (HNE-HDL) or MDA-modified HDL (MDA-HDL) for 24 h. Contrary to native HDL, oxidized forms of HDL were unable to prevent foam cell formation as shown by increased Oil red-O staining. Next, using a Boyden chamber assay, we demonstrated that acro- and MDA-HDL had impaired abilities to promote macrophage migration (64% and 67% of native HDL cell migration, respectively). Finally, using a secreted alkaline phosphatase reporter THP-1 cell-based assay, we determined that acro-HDL promotes activation of the pro-inflammatory NFkappaB pathway. Interestingly, immunoblot and quantitative RT-PCR analyses revealed that incubation of macrophages with acro- and MDA-HDL leads to increased expression of the pro-atherogenic receptor, cluster of differentiation 36 (CD36). Therefore, we repeated the foam cell formation and migration experiments using similar ligands, but this time, in CD36-null peritoneal macrophages. We found that both of these functions were dependent on CD36; however, the extent of the functional changes varied based on the type of oxidative modification present on HDL. In conclusion, modification of HDL with reactive aldehydes generates a particle that has pro-atherogenic effects in macrophages, many of which are dependent on CD36.

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