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Signaling Pathways Reciprocally Control Chlamydia pneumoniae-Induced Acceleration of Atherosclerosis1
* Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, CA 90048;
Medical Clinic II, University of Erlangen-Nuremburg, Erlangen, Germany;
Department of Pathology, University of California, Irvine, California 92697;
Molecular Biology Institute and
¶ Division of Cardiology, University of California, Los Angeles, CA, 90095;
|| Division of Cardiology and Oppenheimer Atherosclerosis Research Center, Cedars-Sinai Medical Center and the University of California, Los Angeles, CA 90048; and
# Department of Microbiology and Immunology, Aichi Medical University, Nagakute, Japan
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 
(LXR) signaling pathways. We infected ApoE–/– mice and ApoE–/– mice that also lacked TLR2, TLR4, MyD88, or LXR 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-. 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–/–LXR–/– double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXR appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute (NHLBI) (5R01AI058128, 5R01AI067995, and RO1HL66436 to M.A.) and the NHLBI (2P01HL030568 and 5R01HL066088 to P.T.). P.T. is an investigator of the Howard Hughes Medical Institute. A. Y. is funded by the German Heart Foundation.
2 Address correspondence and reprint requests to Dr. Moshe Arditi, Cedars Sinai Medical Center, Division of Pediatric Infectious Diseases and Immunology, 8700 Beverly Boulevard, Room 4221, Los Angeles, CA 90048. E-mail address: moshe.arditi{at}cshs.org
3 Abbreviations used in this paper: LXR, liver X receptor; ApoE, apolipoprotein E; DC, dendritic cell; EC, endothelial cell; IFU, inclusion-forming unit; MOI, multiplicity of infection; ox-LDL, oxidized low-density lipoprotein.
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