scholarly journals Chlamydia pneumoniae-Induced Macrophage Foam Cell Formation Is Mediated by Toll-Like Receptor 2

2006 ◽  
Vol 75 (2) ◽  
pp. 753-759 ◽  
Author(s):  
Fei Cao ◽  
Antonio Castrillo ◽  
Peter Tontonoz ◽  
Fabio Re ◽  
Gerald I. Byrne
Keyword(s):  
Chlamydia Pneumoniae ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Toll Like Receptor ◽  
Macrophage Foam Cell ◽  
E Coli ◽  
Toll Like Receptor 2 ◽  
Ce Content

ABSTRACT Chlamydia pneumoniae induces macrophage foam cell formation, a hallmark of early atherosclerosis, in the presence of low-density lipoprotein (LDL). This study examined the role that Toll-like receptor 2 (TLR2) and TLR4 may play in pathogen-induced foam cell formation. Murine macrophage RAW 264.7 cells either infected with C. pneumoniae or treated with the TLR4 ligand E. coli lipopolysaccharide (LPS) or the TLR2 ligand Pam3-Cys-Ala-Gly-OH (Pam) became Oil Red O-stained foam cells and showed increased cholesteryl ester (CE) content when cocultured with LDL. In macrophages from TLR2−/− mice, foam cells were induced by Escherichia coli LPS but not by C. pneumoniae or Pam. Conversely, C. pneumoniae or Pam, but not E. coli LPS, induced foam cells in the TLR4-deficient GG2EE macrophage cell line, suggesting that C. pneumoniae elicits foam cell formation predominantly via TLR2. Enhancing cholesterol efflux using the liver X receptor (LXR) agonist GW3965 significantly decreased the CE content of cells exposed to each of the three TLR ligands (C. pneumoniae, Pam, and E. coli LPS). Overall, our results suggest that activation of the LXR signaling pathway may affect potentially atherogenic processes modulated by the TLR ligands.

Abstract 126: Chlamydia Pneumoniae Induces Foam Cell Formation Of Macrophages By Activating The TLR4/TRIF/IRF3 Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Shuang Chen ◽  
Rosalinda Sorrentino ◽  
Kenichi Shimada ◽  
Timothy Crother ◽  
Moshe Arditi
Keyword(s):  
Transcriptional Control ◽  
Chlamydia Pneumoniae ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Peritoneal Macrophages ◽  
Foam Cell Formation ◽  
Toll Like Receptors ◽  
Macrophage Foam Cell

Background: Chlamydia pneumoniae (CP) induces macrophage foam cell formation (FCF), a key event in early atherosclerosis, in the presence of low-density lipoprotein (LDL). Recent studies have indicated the role of Toll-Like Receptors in atherogenesis. Liver X receptors (LXR) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism and determinants of atherosclerosis. Induction of LXR-activated genes has also been shown to influence the pathogen pattern recognition activity of the Toll-like receptors 3 and 4 (TLR3/4). The TLR and the LXR pathways converge on the transcription factor IRF3. Objective: We hypothesized that TLR and the LXR and IRF3 pathways participate in CP infection mediated FCF and acceleration of atherosclerosis, and that the MyD88- independent pathway via TLR4/TRIF and IRF3 play a role in this acceleration. Methods: Peritoneal macrophages were isolated from C57BL/6 wild type (WT) mice, IRF3 −/− mice, TLR4 −/− mice and TRIF −/− mice. Cells were treated with UV killed CP (UVCP, 5x10 5 IFU) with or without ox-LDL (100 μg/ml) in the presence or absence of LXR agonist GW3965 (2nM). LPS (10 ng/ml) and PolyI:C (1μg/ml) were used as positive controls as TLR4 and TLR3 ligands, respectively. FCF was examined by Oil Red O staining. The percentages of foam cells in total macrophages were quantified. Results : FCF was significantly reduced in IRF3−/− cells compared with WT cells stimulated with UVCP plus ox-LDL. Foam cells induced by LPS with ox-LDL were also significantly reduced in IRF3−/− cells compared to WT cells (p<0.05). Furthermore, the synthetic LXR agonist GW3965 significantly diminished CP induced FCF in WT cells. FCF was significantly reduced in TLR4−/− and TRIF−/− macrophages compared to WT cells when stimulated with UVCP with ox-LDL (p<0.05). Conclusion : Chlamydia pneumoniae infection can activate the TLR4/TRIF/IRF3 pathway and does play an important role in CP- mediated foam cell formation in macrophages. Therefore, infections such as the one caused by CP, can trigger the TLR4/TRIF/IRF3 pathway leading to the down regulation of LXRs and shifting of cholesterol transport toward pro-foam cell production and thereby accelerating atherogenesis.. Supported by NIH grants AI 067995 and HL66436 to MA.

scholarly journals Koala Biovar of Chlamydia pneumoniae Infects Human and Koala Monocytes and Induces Increased Uptake of Lipids In Vitro

2001 ◽  
Vol 69 (12) ◽  
pp. 7894-7897 ◽  
Author(s):  
Katie A. Coles ◽  
Peter Timms ◽  
David W. Smith
Keyword(s):  
Chlamydia Pneumoniae ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Low Density ◽  
Human Monocytes

ABSTRACT We examined the ability of the koala biovar of Chlamydia pneumoniae to infect both Hep-2 cells and human monocytes and the effect of infection on the formation of foam cells. The koala biovar produced large inclusions in both human and koala monocytes and in Hep-2 cells. Koala C. pneumoniae induced foam cell formation with and without added low-density lipoprotein, in contrast to TW183, which produced increased foam cell formation only in the presence of low-density lipoprotein.

scholarly journals A Chlamydia pneumoniae Component That Induces Macrophage Foam Cell Formation Is Chlamydial Lipopolysaccharide

1998 ◽  
Vol 66 (11) ◽  
pp. 5067-5072 ◽  
Author(s):  
Murat V. Kalayoglu ◽  
Gerald I. Byrne
Keyword(s):  
Cholesteryl Ester ◽  
Chlamydia Pneumoniae ◽  
Elevated Temperatures ◽  
Foam Cell ◽  
Cell Formation ◽  
Disease Process ◽  
Foam Cell Formation ◽  
Human Macrophage ◽  
Macrophage Foam Cell ◽  
Cholesteryl Ester Accumulation

ABSTRACT Chlamydia pneumoniae infection is associated with atherosclerotic heart and vessel disease, but a causal relationship between this pathogen and the disease process has not been established. Recently, it was reported that C. pneumoniae induces human macrophage foam cell formation, a key event in early atheroma development, suggesting a role for the organism in atherogenesis. This study further examines C. pneumoniae-induced foam cell formation in the murine macrophage cell line RAW-264.7. Infected RAW cells accumulated cholesteryl esters when cultured in the presence of low-density lipoprotein in a manner similar to that described for human macrophages. Exposure of C. pneumoniae elementary bodies to periodate, but not elevated temperatures, inhibited cholesteryl ester accumulation, suggesting a role for chlamydial lipopolysaccharide (cLPS) in macrophage foam cell formation. Purified cLPS was found to be sufficient to induce cholesteryl ester accumulation and foam cell formation. Furthermore, the LPS antagonist lipid X inhibited C. pneumoniae and cLPS-induced lipid uptake. These data indicate that cLPS is a C. pneumoniae component that induces macrophage foam cell formation and suggest that infected macrophages chronically exposed to cLPS may accumulate excess cholesterol to contribute to atheroma development.

Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages

2018 ◽  
Vol 46 (01) ◽  
pp. 87-106 ◽  
Author(s):  
Hung-Chih Lin ◽  
Chong-Kuei Lii ◽  
Hui-Chun Chen ◽  
Ai-Hsuan Lin ◽  
Ya-Chen Yang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Cholesterol Accumulation ◽  
Macrophage Foam Cell ◽  
Macrophage Foam Cells ◽  
Mrna And Protein Expression ◽  
Anti Inflammatory

oxLDL is involved in the pathogenesis of atherosclerotic lesions through cholesterol accumulation in macrophage foam cells. Andrographolide, the bioactive component of Andrographis paniculata, possesses several biological activities such as anti-inflammatory, anti-oxidant, and anticancer functions. Scavenger receptors (SRs), including class A SR (SR-A) and CD36, are responsible for the internalization of oxLDL. In contrast, receptors for reverse cholesterol transport, including ABCA1 and ABCG1, mediate the efflux of cholesterol from macrophage foam cells. Transcription factor liver X receptor [Formula: see text] (LXR[Formula: see text] plays a key role in lipid metabolism and inflammation as well as in the regulation of ABCA1 and ABCG1 expression. Because of the contribution of inflammation to macrophage foam cell formation and the potent anti-inflammatory activity of andrographolide, we hypothesized that andrographolide might inhibit oxLDL-induced macrophage foam cell formation. The results showed that andrographolide reduced oxLDL-induced lipid accumulation in macrophage foam cells. Andrographolide decreased the mRNA and protein expression of CD36 by inducing the degradation of CD36 mRNA; however, andrographolide had no effect on SR-A expression. In contrast, andrographolide increased the mRNA and protein expression of ABCA1 and ABCG1, which were dependent on LXR[Formula: see text]. Andrographolide enhanced LXR[Formula: see text] nuclear translocation and DNA binding activity. Treatment with the LXR[Formula: see text] antagonist GGPP and transfection with LXR[Formula: see text] siRNA reversed the ability of andrographolide to stimulate ABCA1 and ABCG1 protein expression. In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.

scholarly journals Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 832
Author(s):  
Michishige Terasaki ◽  
Hironori Yashima ◽  
Yusaku Mori ◽  
Tomomi Saito ◽  
Yoshie Shiraga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
U937 Cells ◽  
Cyclin Dependent Kinase ◽  
Macrophage Foam Cell ◽  
Cyclin Dependent Kinase 5 ◽  
Gip Receptor ◽  
Cd36 Gene

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and CD36 expression in, macrophages extracted from GIP receptor-deficient (Gipr−/−) and Gipr+/+ mice and cultured human U937 macrophages by using an agonist for GIP receptor, [D-Ala2]GIP(1–42). Foam cell formation evaluated by esterification of free cholesterol to cholesteryl ester and CD36 gene expression in macrophages isolated from Gipr+/+ mice infused subcutaneously with [D-Ala2]GIP(1–42) were significantly suppressed compared with vehicle-treated mice, while these beneficial effects were not observed in macrophages isolated from Gipr−/− mice infused with [D-Ala2]GIP(1–42). When macrophages were isolated from Gipr+/+ and Gipr−/− mice, and then exposed to [D-Ala2]GIP(1–42), similar results were obtained. [D-Ala2]GIP(1–42) attenuated ox-LDL uptake of, and CD36 gene expression in, human U937 macrophages as well. Gene expression level of cyclin-dependent kinase 5 (Cdk5) was also suppressed by [D-Ala2]GIP(1–42) in U937 cells, which was corelated with that of CD36. A selective inhibitor of Cdk5, (R)-DRF053 mimicked the effects of [D-Ala2]GIP(1–42) in U937 cells. The present study suggests that GIP could inhibit foam cell formation of macrophages by suppressing the Cdk5-CD36 pathway via GIP receptor.

scholarly journals Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs

2021 ◽  
Vol 22 (5) ◽  
pp. 2529
Author(s):  
Amin Javadifar ◽  
Sahar Rastgoo ◽  
Maciej Banach ◽  
Tannaz Jamialahmadi ◽  
Thomas P. Johnston ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Special Focus ◽  
Lipid Uptake ◽  
Therapeutic Goals ◽  
Expression Of Genes

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.

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