The activation of liver X receptors inhibits toll-like receptor-9-induced foam cell formation

2009 ◽  
pp. n/a-n/a ◽  
Author(s):  
Rosalinda Sorrentino ◽  
Silvana Morello ◽  
Eduardo Bonavita ◽  
Aldo Pinto
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Liver X Receptors ◽  
Toll Like Receptor ◽  
X Receptors

scholarly journals Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Zhongli Chen ◽  
Qiqi Xue ◽  
Lijuan Cao ◽  
Yanpin Wang ◽  
Yuanyuan Chen ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cell Phenotype ◽  
Toll Like Receptor ◽  
Oxidized Low Density Lipoprotein ◽  
Kinase Activation ◽  
Ros Accumulation

Oxidized low-density lipoprotein (oxLDL) induced a foam-cell-like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptor- (Tlr-) mediated cellular alterations. However, the role of Tlr4 in foam cell formation and underlying molecular pathways has not been comprehensively elucidated. To further investigate the mechanism, VSMCs were incubated with different doses of oxLDL, and then, the lipid, reactive oxygen species (ROS) accumulation, Tlr family genes, and the foam cell phenotype were explored. We observed that oxLDL induced foam cell-like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. Furthermore, in the Tlr family, Tlr4 demonstrated the strongest upregulation under oxLDL stimulation. Simultaneously, oxLDL induced activation of Src, higher expression of Nox2, and lower expression of Mnsod, Sirt1, and Sirt3. By interfering the TLR4 expression, the phenotype alteration, lipid accumulation in VSMCs, and Src kinase activation induced by oxLDL were abolished. After interfering Src activation, the oxLDL-induced lipid accumulation and foam cell phenotype in VSMCs were also alleviated. Furthermore, the ROS accumulation, upregulated Nox2 expression, downregulated Sirt1, Sirt3, and Mnsod expression in VSMCs under oxLDL stimulation were also relieved after the knockdown of Tlr4. Additionally, overexpression of Sirt1 and Sirt3 ameliorated the ROS accumulation and foam cell-like marker expression in VSMCs. These results demonstrated that beyond its familiar role in regulating inflammation response, Tlr4 is a critical regulator in oxLDL-induced foam cell formation in VSMCs via regulating Src kinase activation as well as Sirt1 and Sirt3 expression.

A Toll-like receptor 9-mediated pathway stimulates perilipin 3 (TIP47) expression and induces lipid accumulation in macrophages

2010 ◽  
Vol 299 (4) ◽  
pp. E593-E600 ◽  
Author(s):  
Jian-Qiu Gu ◽  
Di-Fei Wang ◽  
Xiao-Guang Yan ◽  
Wei-Li Zhong ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Foam Cell ◽  
Cell Formation ◽  
Cholesterol Content ◽  
Foam Cell Formation ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Triglyceride Accumulation ◽  
Pat Proteins ◽  
Accumulation Of Lipids

Excessive accumulation of lipids in macrophages results in formation of foam cells and is a hallmark of atherosclerosis. The PAT family of proteins has been implicated in this process, but details of their involvement in foam cell formation have not been fully elucidated. One of dominant members of the PAT proteins, perilipin 3 (TIP47), is likely to be involved in such a regulatory mechanism. In this study, we demonstrated that the Toll-like receptor 9 (TLR9)-mediated pathway stimulates perilipin 3 expression and accumulation of lipids, especially triglycerides, in macrophages. Oligodeoxynucleotide (ODN) 1826, a ligand of TLR9, significantly enhanced perilipin 3 expression in RAW264.7 cells, and chloroquine, a TLR9 inhibitor, almost completely inhibited ODN1826-induced perilipin 3 expression. The inhibitors of c-jun NH2-terminal kinase and PI 3-kinase suppressed the level of perilipin 3 mRNA induced by ODN1826. ODN1826 induced the expression of IL-1α and IFNβ, both of which increased perilipin 3 expression. Antibodies against these cytokines suppressed the ODN1826-induced perilipin 3 mRNA levels. These results suggest that the expression of perilipin 3 in macrophages is in part regulated through the TLR9-mediated mechanism. Furthermore, ODN1826 increased intracellular lipid accumulation in the presence of oxLDL, which was reduced by perilipin 3 siRNA. Perilipin 3 expression was not stimulated by oxLDL. Depletion of perilipin 3 by siRNA specifically reduced triglyceride content in the cells but not cholesterol content, indicating that perilipin 3 is involved mainly in triglyceride accumulation. In conclusion, the TLR9-mediated pathway facilitates foam cell formation in part through increased expression of perilipin 3.

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.

scholarly journals TLR4 (Toll-Like Receptor 4)-Dependent Signaling Drives Extracellular Catabolism of LDL (Low-Density Lipoprotein) Aggregates

2020 ◽  
Vol 40 (1) ◽  
pp. 86-102 ◽  
Author(s):  
Rajesh K. Singh ◽  
Abigail S. Haka ◽  
Arky Asmal ◽  
Valéria C. Barbosa-Lorenzi ◽  
Inna Grosheva ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Low Density ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

Objective: Aggregation and modification of LDLs (low-density lipoproteins) promote their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of agLDL (aggregated LDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse. Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites, such as cholesterol, promotes foam cell formation, a process that drives atherogenesis. Furthermore, there is accumulating evidence for the involvement of TLR4 (Toll-like receptor 4) and its adaptor protein MyD88 (myeloid differentiation primary response 88) in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the lysosomal synapse and foam cell formation. Approach and Results: Using bone marrow–derived macrophages from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment, and foam cell formation. Using siRNA (small interfering RNA), pharmacological inhibition and knockout bone marrow–derived macrophages, we implicate SYK (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and Akt in agLDL catabolism using the lysosomal synapse. Using bone marrow transplantation of LDL receptor knockout mice with TLR4 knockout bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL. Conclusions: We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the lysosomal synapse, catabolism of agLDL, and lipid accumulation in vitro and in vivo.

Sign in / Sign up

Export Citation Format

Share Document