title: Toll-Like Receptor 9-Mediated Inflammation Triggers Alveolar Bone Loss in Experimental Murine Periodontitis.
abstract: Chronic periodontitis is a local inflammatory disease induced by a dysbiotic microbiota and leading to destruction of the tooth-supporting structures. Microbial nucleic acids are abundantly present in the periodontium, derived through release after phagocytic uptake of microbes and/or from biofilm-associated extracellular DNA. Binding of microbial DNA to its cognate receptors, such as Toll-like receptor 9 (TLR9), can trigger inflammation. In this study, we utilized TLR9 knockout (TLR9(-/-)) mice and wild-type (WT) controls in a murine model of Porphyromonas gingivalis-induced periodontitis and report the first in vivo evidence that TLR9 signaling mediates the induction of periodontal bone loss. P. gingivalis-infected WT mice exhibited significantly increased bone loss compared to that in sham-infected WT mice or P. gingivalis-infected TLR9(-/-) mice, which were resistant to bone loss. Consistent with this, the expression levels of interleukin 6 (IL-6), tumor necrosis factor (TNF), and receptor-activator of nuclear factor kappa B ligand (RANKL) were significantly elevated in the gingival tissues of the infected WT mice but not in infected TLR9(-/-) mice compared to their levels in controls. Ex vivo studies using splenocytes and bone marrow-derived macrophages revealed significantly diminished cytokine production in TLR9(-/-) cells relative to the cytokine production in WT cells in response to P. gingivalis, thereby implicating TLR9 in inflammatory responses to this organism. Intriguingly, compared to the cytokine production in WT cells, TLR9(-/-) cells exhibited significantly decreased proinflammatory cytokine production upon challenge with lipopolysaccharide (LPS) (TLR4 agonist) or Pam3Cys (TLR2 agonist), suggesting possible cross talk between TLR9, TLR4, and TLR2. Collectively, our results provide the first proof-of-concept evidence implicating TLR9-triggered inflammation in periodontal disease pathogenesis, thereby identifying a new potential therapeutic target to control periodontal inflammation.
authors.affiliation: Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kim
authors.affiliation: Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Xia-Juan
authors.affiliation: Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Crump
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
authors.affiliation: Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA ssahingur@vcu.edu.
authors.forename: Sinem E
authors.initials: SE
authors.lastname: Sahingur
mesh_terms: D016301:Alveolar Bone Loss; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010518:Periodontitis / Q000473:pathology*; D016966:Porphyromonas gingivalis / Q000254:growth & development*; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016207:Cytokines; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9