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PMID: 18981139 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TLR/MyD88 and liver X receptor alpha signaling pathways reciprocally control Chlamydia pneumoniae-induced acceleration of atherosclerosis.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 181 ·No. 10 ·2008-11-15 ·Pages 7176-85

Naiki Y, Sorrentino R, Wong MH, Michelsen KS, Shimada K, Chen S, Yilmaz A, Slepenkin A, Schröder NW, Crother TR, Bulut Y, Doherty TM, Bradley M, Shaposhnik Z, Peterson EM, Tontonoz P, Shah PK, Arditi M

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 alpha (LXRalpha) signaling pathways. We infected ApoE(-/-) mice and ApoE(-/-) mice that also lacked TLR2, TLR4, MyD88, or LXRalpha 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-alpha. 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(-/-)LXRalpha(-/-) double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-alpha. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXRalpha appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection.

MeSH Terms
Animals Aorta/immunology,pathology Apolipoproteins E/deficiency,genetics Atherosclerosis/metabolism,microbiology Chlamydia Infections/complications,metabolism Chlamydophila pneumoniae Cytokines/blood,immunology DNA-Binding Proteins/genetics,metabolism Dendritic Cells/immunology,metabolism Fluorescent Antibody Technique Gene Expression Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis,genetics Hypercholesterolemia/complications Immunohistochemistry Liver X Receptors Mice Mice, Knockout Myeloid Differentiation Factor 88/genetics,metabolism Oligonucleotide Array Sequence Analysis Orphan Nuclear Receptors Receptors, Cytoplasmic and Nuclear/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/physiology Toll-Like Receptors/genetics,metabolism
Chemicals
Apolipoproteins E Cytokines DNA-Binding Proteins Liver X Receptors Myd88 protein, mouse Myeloid Differentiation Factor 88 Nr1h3 protein, mouse Orphan Nuclear Receptors Receptors, Cytoplasmic and Nuclear Toll-Like Receptors Granulocyte-Macrophage Colony-Stimulating Factor
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Naiki Yoshikazu
Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, CA 90048, USA.
Sorrentino Rosalinda
Wong Michelle H
Michelsen Kathrin S
Shimada Kenichi
Chen Shuang
Yilmaz Atilla
Slepenkin Anatoly
Schröder Nicolas W J
Crother Timothy R
Bulut Yonca
Doherty Terence M
Bradley Michelle
Shaposhnik Zory
Peterson Ellena M
Tontonoz Peter
Shah Prediman K
Arditi Moshe
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.181.10.7176
Published
2008-11-15
Pages
7176-85
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2683843
Subset
IM
Grants
NIAID NIH HHS · R01 AI058128 · United States
NHLBI NIH HHS · R01 HL066436-01 · United States
NHLBI NIH HHS · R01 HL066436-02 · United States
NIAID NIH HHS · 5R01AI067995 · United States
NIAID NIH HHS · R01 AI067995 · United States
NHLBI NIH HHS · R01 HL066436 · United States
NHLBI NIH HHS · 2P01HL030568 · United States
NHLBI NIH HHS · R01 HL066436-04 · United States
NHLBI NIH HHS · R01 HL066088-05 · United States
NHLBI NIH HHS · 5R01HL066088 · United States
NHLBI NIH HHS · R01HL66436 · United States
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · R01 HL066088 · United States
NHLBI NIH HHS · P01 HL030568-250012 · United States
NHLBI NIH HHS · R01 HL066436-03 · United States
NIAID NIH HHS · 5R01AI058128 · United States
NHLBI NIH HHS · R01 HL066436-02S1 · United States
NHLBI NIH HHS · P01 HL030568 · United States
NIAID NIH HHS · R01 AI067995-03 · United States
NIAID NIH HHS · R01 AI058128-05 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.181.10.7176 PMC Full Text View journal details
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