title: Protective role for TLR4 signaling in atherosclerosis progression as revealed by infection with a common oral pathogen.
abstract: Clinical and epidemiological studies have implicated chronic infections in the development of atherosclerosis. It has been proposed that common mechanisms of signaling via TLRs link stimulation by multiple pathogens to atherosclerosis. However, how pathogen-specific stimulation of TLR4 contributes to atherosclerosis progression remains poorly understood. In this study, atherosclerosis-prone apolipoprotein-E null (ApoE(-/-)) and TLR4-deficient (ApoE(-/-)TLR4(-/-)) mice were orally infected with the periodontal pathogen Porphyromonas gingivalis. ApoE(-/-)TLR4(-/-) mice were markedly more susceptible to atherosclerosis after oral infection with P. gingivalis. Using live animal imaging, we demonstrate that enhanced lesion progression occurs progressively and was increasingly evident with advancing age. Immunohistochemical analysis of lesions from ApoE(-/-)TLR4(-/-) mice revealed an increased inflammatory cell infiltrate composed primarily of macrophages and IL-17 effector T cells (Th17), a subset linked with chronic inflammation. Furthermore, enhanced atherosclerosis in TLR4-deficient mice was associated with impaired development of Th1 immunity and regulatory T cell infiltration. In vitro studies suggest that the mechanism of TLR4-mediated protective immunity may be orchestrated by dendritic cell IL-12 and IL-10, which are prototypic Th1 and regulatory T cell polarizing cytokines. We demonstrate an atheroprotective role for TLR4 in response to infection with the oral pathogen P. gingivalis. Our results point to a role for pathogen-specific TLR signaling in chronic inflammation and atherosclerosis.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Chie
authors.initials: C
authors.lastname: Hayashi
authors.forename: George
authors.initials: G
authors.lastname: Papadopoulos
authors.forename: Cynthia V
authors.initials: CV
authors.lastname: Gudino
authors.forename: Ellen O
authors.initials: EO
authors.lastname: Weinberg
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Barth
authors.forename: Andrés G
authors.initials: AG
authors.lastname: Madrigal
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Hua
authors.initials: H
authors.lastname: Ning
authors.forename: Michael
authors.initials: M
authors.lastname: LaValley
authors.forename: Frank C
authors.initials: FC
authors.lastname: Gibson
authors.forename: James A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Genco
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016866:Bacteroidaceae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D005891:Gingivitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016966:Porphyromonas gingivalis / Q000276:immunology* / Q000472:pathogenicity; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4