title: Global TLR2 and 4 deficiency in mice impacts bone resorption, inflammatory markers and atherosclerosis to polymicrobial infection.
abstract: Toll-like-receptors (TLRs) play a significant role in the generation of a specific innate immune response against invading pathogens. TLR2 and TLR4 signaling contributes to infection-induced inflammation in periodontal disease (PD) and atherosclerosis. Observational studies point towards a relationship between PD and atherosclerosis, but the role of TLR2 and TLR4 in the recognition of multiple oral pathogens and their modulation of host response leading to atherosclerosis are not clear. We evaluated the role of TLR2 and TLR4 signaling in the induction of both PD and atherosclerosis in TLR2-/-and TLR4-/-mice to polymicrobial infection with periodontal pathogens Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum. Polybacterial infections have established gingival colonization in TLR2-/-and TLR4-/-mice and induction of a pathogen-specific immunoglobulin G immune response. But TLR deficiency dampened accelerated alveolar bone resorption and intrabony defects, indicating a central role in infection-induced PD. Periodontal bacteria disseminated from gingival tissue to the heart and aorta through intravascular dissemination; however, there was no increase in atherosclerosis progression in the aortic arch. Polybacterial infection does not alter levels of serum risk factors such as oxidized low-density lipoprotein, nitric oxide, and lipid fractions in both mice. Polymicrobial-infected TLR2-/-mice demonstrated significant levels (P < 0.05 to P < 0.01) of T helper type 2 [transforming growth factor-β1, macrophage inflammatory protein-3α, interleukin-13 (IL-13)] and T helper type 17 (IL-17, IL-21, IL-22, IL-23) splenic T-cell cytokine responses. Increased heat-shock protein expression, hspa1a for Hsp 70, was observed for both TLR2-/-and TLR4-/-mice. This study supports a role for TLR2 and TLR4 in PD and atherosclerosis, corroborating an intricate association between two inflammatory diseases.
authors.affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Chukkapalli
authors.affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Velsko
authors.affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Rivera-Kweh
authors.affiliation: Division of Periodontics and Dental Hygiene, University of British Columbia, Vancouver, BC, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Larjava
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.|Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Lucas
authors.affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, USA.|Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Kesavalu
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*; D001862:Bone Resorption / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*; D060085:Coinfection / Q000276:immunology* / Q000382:microbiology; D016207:Cytokines / Q000097:blood; D016967:Fusobacterium nucleatum / Q000276:immunology; D006360:Heat-Shock Proteins / Q000097:blood; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*; D008077:Lipoproteins, LDL / Q000097:blood; D051379:Mice; D009569:Nitric Oxide / Q000097:blood; D010510:Periodontal Diseases / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000276:immunology; D000070436:Tannerella forsythia / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D048373:Treponema denticola / Q000276:immunology
chemical_list: D016207:Cytokines; D006360:Heat-Shock Proteins; D008077:Lipoproteins, LDL; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide
keywords: Fusobacterium nucleatum
  ; Porphyromonas gingivalis
  ; Tannerella forsythia
  ; Toll-like receptor-2-deficient mice; Toll-like receptor-4-deficient mice; Treponema denticola
  ; atherosclerosis; periodontal disease; polymicrobial infection