Inflammation is essential for effective control of infection;however, in chronic infectious diseases such as periodontal disease (PD), the resulting inflammation fails to adequately protect the host. The bacterium most associated with chronic generalized PD is Porphyromonas gingivalis. PD lesions are identified by loss of periodontal attachment, oral bone loss, significant influx of mononuclear cells, and expression of inflammatory markers at sites of disease. Expression of these pro-inflammatory molecules is controlled in part via innate immune pattern recognition receptors including the toll-like receptors (TLR). In vitro studies support roles for TLR signaling pathways regulate inflammation in response to P. gingivalis;however, these pathways are poorly defined. Therefore, a more detailed understanding of the host factors that regulate inflammation in response to P. gingivalis in the context of bone remodeling is needed. In addition to the local inflammatory lesions of the oral cavity associated with P. gingivalis infection, recent clinical and animal model data support a role for infection by organisms such as P. gingivalis and others including Chlamydophila pneumoniae with accelerated vascular plaque accumulation. Atherosclerosis is a complex inflammatory disease. Regulation of inflammation is thought to be key to preventing this disease. The nuclear hormone receptor liver X receptor (LXR) plays a key role in regulating expression of genes involved in cellular cholesterol efflux. Recently, a second function for LXR, namely regulation of TLRdependent inflammatory pathways has been identified. As innate immune signaling via TLRs is implicated in atherosclerosis, PD, and host response to P. gingivalis, and LXR is a regulator of TLR mediated inflammation, we speculated that LXR could influences both oral bone loss and atherosclerosis elicited by P. gingivalis. Here we propose an interrelated set of aims to test the hypothesis that LXR regulates inflammatory gene expression and bone loss elicited by P. gingivalis;moreover, LXR plays a central role in infection-accelerated chronic inflammatory vascular plaque accumulation. These studies will provide a detailed understanding of the role played by LXR in regulating inflammation that accompanies P. gingivalis infection.

Public Health Relevance

Porphyromonas gingivalis is associated with the oral chronic inflammatory diseases periodontal disease and the vascular inflammatory disease atherosclerosis. The nuclear hormone receptor liver X receptor (LXR) is a transcriptional regulator of genes involved in cholesterol mobilization, inflammation, and host response to infection. Bases on these known activities of LXR and our preliminary data, we will define the role of LXR in inflammation, oral bone loss, and atherosclerosis elicited by P. gingivalis.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston University
United States
Zip Code
Shaik-Dasthagirisaheb, Y B; Huang, N; Weinberg, E O et al. (2015) Aging and contribution of MyD88 and TRIF to expression of TLR pathway-associated genes following stimulation with Porphyromonas gingivalis. J Periodontal Res 50:89-102
Huang, Nasi; Gibson 3rd, Frank C (2014) Immuno-pathogenesis of Periodontal Disease: Current and Emerging Paradigms. Curr Oral Health Rep 1:124-132
Koupenova, Milka; Vitseva, Olga; MacKay, Christopher R et al. (2014) Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 124:791-802
Shaik-Dasthagirisaheb, Yazdani B; Huang, Nasi; Gibson 3rd, Frank C (2014) Inflammatory response to Porphyromonas gingivalis partially requires interferon regulatory factor (IRF) 3. Innate Immun 20:312-9
Beaulieu, Lea M; Lin, Elaine; Mick, Eric et al. (2014) Interleukin 1 receptor 1 and interleukin 1? regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans. Arterioscler Thromb Vasc Biol 34:552-64
Clancy, Lauren; Freedman, Jane E (2014) New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer. J Thromb Thrombolysis 37:12-6
Freedman, Jane E (2014) Inherited dysfunctional nitric oxide signaling and the pathobiology of atherothrombotic disease. Circ Res 114:1372-3
He, Xianbao; Berland, Robert; Mekasha, Samrawit et al. (2013) The sst1 resistance locus regulates evasion of type I interferon signaling by Chlamydia pneumoniae as a disease tolerance mechanism. PLoS Pathog 9:e1003569
Freedman, Jane E; Tanriverdi, Kahraman (2013) Defining miRNA targets: balancing simplicity with complexity. Circulation 127:2075-7
Shaik-Dasthagirisaheb, Y B; Huang, N; Baer, M T et al. (2013) Role of MyD88-dependent and MyD88-independent signaling in Porphyromonas gingivalis-elicited macrophage foam cell formation. Mol Oral Microbiol 28:28-39

Showing the most recent 10 out of 13 publications