TLR/MyD88 and liver X receptor alpha signaling pathways reciprocally control Chlamydia pneumoniae-induced acceleration of atherosclerosis.
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.
Naiki
Yoshikazu
Y
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
R
Wong
Michelle H
MH
Michelsen
Kathrin S
KS
Shimada
Kenichi
K
Chen
Shuang
S
Yilmaz
Atilla
A
Slepenkin
Anatoly
A
Schröder
Nicolas W J
NW
Crother
Timothy R
TR
Bulut
Yonca
Y
Doherty
Terence M
TM
Bradley
Michelle
M
Shaposhnik
Zory
Z
Peterson
Ellena M
EM
Tontonoz
Peter
P
Shah
Prediman K
PK
Arditi
Moshe
M
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism / Q000382:microbiology*; D002690:Chlamydia Infections / Q000150:complications* / Q000378:metabolism; D016993:Chlamydophila pneumoniae; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D006937:Hypercholesterolemia / Q000150:complications; D007150:Immunohistochemistry; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D016207:Cytokines; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051193:Toll-Like Receptors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor