Pathogen-mediated inflammatory atherosclerosis is mediated in part via Toll-like receptor 2-induced inflammatory responses.
Studies in humans have established that polymorphisms in genes encoding the innate immune Toll-like receptors (TLRs) are associated with inflammatory atherosclerosis. In hyperlipidemic mice, TLR2 and TLR4 have been reported to contribute to atherosclerosis progression. Human and mouse studies support a role for the oral pathogen Porphyromonas gingivalis in atherosclerosis, although the mechanisms by which this pathogen stimulates inflammatory atherosclerosis via innate immune system activation is not known. Using a genetically defined apolipoprotein E-deficient (ApoE(-/-)) mouse model we demonstrate that pathogen-mediated inflammatory atherosclerosis occurs via both TLR2-dependent and TLR2-independent mechanisms. P. gingivalis infection in mice possessing functional TLR2 induced the accumulation of macrophages as well as inflammatory mediators including CD40, IFN-gamma and the pro-inflammatory cytokines IL-1 beta, IL-6 and tumor necrosis factor-alpha in atherosclerotic lesions. The expression of these inflammatory mediators was reduced in atherosclerotic lesions from P. gingivalis-infected TLR2-deficient (TLR2(-/-)) mice. These studies provide a mechanistic link between an innate immune receptor and pathogen-accelerated atherosclerosis by a clinically and biologically relevant bacterial pathogen.
Hayashi
Chie
C
Department of Medicine, Sections of Infectious Diseases, Boston University School of Medicine, Boston, MA 02118, USA.
Madrigal
Andres G
AG
Liu
Xinyan
X
Ukai
Takashi
T
Goswami
Sulip
S
Gudino
Cynthia V
CV
Gibson
Frank C
FC
Genco
Caroline A
CA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D016866:Bacteroidaceae Infections / Q000276:immunology / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000382:microbiology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016966:Porphyromonas gingivalis / Q000276:immunology / Q000472:pathogenicity*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D051195:Toll-Like Receptor 2