TLR/MyD88 and Liver X Receptor α Signaling Pathways Reciprocally Control Chlamydia pneumoniae-Induced Acceleration of Atherosclerosis

Abstract

Experimental and clinical studies link Chlamydia pneumoniae infection to atherogenesis and atherothrombotic events, but the underlying mechanisms are unclear. We tested the hypothesis that C. pneumoniae-induced acceleration of atherosclerosis in apolipoprotein E (ApoE)−/− mice is reciprocally modulated by activation of TLR-mediated innate immune and liver X receptor α (LXRα) signaling pathways. We infected ApoE−/− mice and ApoE−/− mice that also lacked TLR2, TLR4, MyD88, or LXRα intranasally with C. pneumoniae followed by feeding of a high fat diet for 4 mo. Mock-infected littermates served as controls. Atherosclerosis was assessed in aortic sinuses and in en face preparation of whole aorta. The numbers of activated dendritic cells (DCs) within plaques and the serum levels of cholesterol and proinflammatory cytokines were also measured. C. pneumoniae infection markedly accelerated atherosclerosis in ApoE-deficient mice that was associated with increased numbers of activated DCs in aortic sinus plaques and higher circulating levels of MCP-1, IL-12p40, IL-6, and TNF-α. In contrast, C. pneumoniae infection had only a minimal effect on atherosclerosis, accumulation of activated DCs in the sinus plaques, or circulating cytokine increases in ApoE−/− mice that were also deficient in TLR2, TLR4, or MyD88. However, C. pneumoniae-induced acceleration of atherosclerosis in ApoE−/− mice was further enhanced in ApoE−/−LXRα−/− double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-α. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXRα appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection.

GroEL1, a Heat Shock Protein 60 of Chlamydia pneumoniae, Induces Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 Expression in Endothelial Cells and Enhances Atherogenesis in Hypercholesterolemic Rabbits

“…It is known that pathogens such as C. pneumoniae can induce macrophage foam cell formation (28), an effect that might be increased if an individual has been infected by multiple pathogens (5). TLR/ MyD88 and liver X receptor signaling pathways reciprocally control C. pneumoniae-induced acceleration of atherosclerosis (29). It has been hypothesized that the infectious pathogen contains proteins that are homologous to parts of the host proteins, resulting in an immune response called infection-induced molecular mimicry (30).…”

Plasmacytoid Dendritic Cells Prevent Cigarette Smoke and Chlamydophila pneumoniae–Induced Th2 Inflammatory Responses

“…The C57BL/6 wild-type and TLR2 knockout (KO) mice were purchased from Jackson Laboratories (Bar Harbor, ME), whereas TLR4 KO mice were kindly provided by Dr. Shizuo Akira (Osaka University, Osaka, Japan). A homogenous population of these mice was established by backcrossing onto the C57BL/6 background for at least 10 generations, as previously described (5). Mice were fed a standard chow diet and housed under specific pathogen-free conditions at Cedars-Sinai Medical Center.…”

“…Chlamydophila pneumoniae is an obligate intracellular bacterium that can also exacerbate atherosclerosis and asthma (5,6). We showed that C. pneumoniae, depending on the infective dose, can lead to either a Th1 response, or can act as an adjuvant to induce allergic sensitization and lead to Th2-like immune responses in mice (6).…”

The Innate Immune Response Mediated by TLRs in Atherosclerosis

“…For example, C. pneumoniae has been isolated from coronary arteries in patients with acute coronary syndrome (Saikku et al, 1988), and in experimental studies, it has been found that infection with C. Pneumoniae increases atherosclerotic plaque size in Apo E −/− mice compared to the controls. It has also been reported that the size of the aortic lesion and the expression of pro-inflammatory cytokines, such as MCP-1, IL-12p40, TNF-, and IL-6, are reduced in ApoE −/− TLR2 −/− , ApoE −/− TLR4 −/− and ApoE −/− MyD88 −/− mice when compared with the ApoE −/− controls infected with C. Pneumoniae (Naiki et al, 2008). Other studies have reported that HSP60 of C. Pneumoniae (cHSP60) reduces the expression and activity of nitric oxide synthase in the endothelial cells of the human coronary artery, which has also been associated with endothelial dysfunction.…”