Chlamydia pneumoniae Hijacks a Host Autoregulatory IL-1β Loop to Drive Foam Cell Formation and Accelerate Atherosclerosis

Background & Objective: Foam cell formation (FCF) due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis. Chlamydia pneumoniae (Cp) promotes FCF in the presence of oxLDL, but the exact molecular mechanisms are still not completely delineated. Recent data indicates that the Nlrp3 inflammasome plays an important role in the formation of atherosclerotic plaques. Here we investigated the role of the Nlrp3 inflammasome during the acceleration of FCF by Cp infection. Methods and Results: In order to determine if the NLRP3 inflammasome played a role in Cp infection induced acceleration of FCF, we treated resident peritoneal macrophages exposed to oxLDL and Cp with the IL-1R antagonist, Anakinra, to block IL-1 signaling. Treatment with Anakinra resulted in a significant reduction in FCF. Nlrp3-/-, Casp1-/-, and WT macrophages were also treated with live Cp in the presence or absence of oxLDL. We found that Nlrp3-/- and Casp1-/- macrophages had significantly less FCF compared with WT cells. Interestingly, both ABCA1 (cholesterol efflux transporter) and its transcription factor, liver X receptor (LXR-α), were increased in Nlrp3-/- and Casp1-/- macrophages compared with WT cells. Addition of rIL-1β to Nlrp3-/- macrophages led to a decrease in ABCA1 expression and greater FCF. Importantly, Il1r-/- macrophages also had greater ABCA1 expression and reduced FCF when exposed to oxLDL and Cp infection. Conclusion: These data suggest that Cp infection facilitates foam cell formation in the presence of oxLDL by producing NLRP3 dependent IL-1 cytokines, which then feed back on the macrophages and interferes with cholesterol efflux by negatively regulating ABCA1. In the absence of IL-1 signaling, the expression of ABCA1 is upregulated leading to greater cholesterol efflux and reduced FCF. Thus we have identified a novel regulatory loop controlling FCF. Understanding these interacting pathways will lead to new therapeutic strategies against atherosclerosis.

Download Full-text

PPARα/γ signaling pathways are involved in Chlamydia pneumoniae-induced foam cell formation via upregulation of SR-A1 and ACAT1 and downregulation of ABCA1/G1

Microbial Pathogenesis ◽

10.1016/j.micpath.2021.105284 ◽

2021 ◽

pp. 105284

Author(s):

Xiaohua Wu ◽

Bei Cheng ◽

Xiaojuan Guo ◽

Qinqin Wu ◽

Shan Sun ◽

...

Keyword(s):

Signaling Pathways ◽

Chlamydia Pneumoniae ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation

Download Full-text

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

Infection and Immunity ◽

10.1128/iai.69.12.7894-7897.2001 ◽

2001 ◽

Vol 69 (12) ◽

pp. 7894-7897 ◽

Cited By ~ 6

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.

Download Full-text

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

Infection and Immunity ◽

10.1128/iai.66.11.5067-5072.1998 ◽

1998 ◽

Vol 66 (11) ◽

pp. 5067-5072 ◽

Cited By ~ 124

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.

Download Full-text

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

Infection and Immunity ◽

10.1128/iai.01386-06 ◽

2006 ◽

Vol 75 (2) ◽

pp. 753-759 ◽

Cited By ~ 106

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.

Download Full-text