Dendritic cells (DC) may play a central role in the pathogenesis of periodontal disease by participating in events that link bacterial stimulation to periodontal bone loss. They may accomplish this by the production of factors that regulate the adaptive and innate immune responses. Furthermore, immature DCs have been reported to function as osteoclasts precursors. Preliminary Data examining DCs in vitro establish that the transcription factor FOXO1 is essential for LPS up-regulation of several cytokines, IL-1, TNF, IL-6, and IL-12 and down-regulation of the anti-inflammatory cytokine IL-10. Moreover, Akt plays an important role in this process by reducing FOXO1 nuclear localization and limiting inflammatory cytokine production in DC. Thus, we propose that FOXO1 is critical in upregulating an inflammatory response in DCs and that a hyper- inflammatory response is prevented by Akt. These findings serve as the basis for the current proposal in which we will test in vivo the hypothesis that the FOXO1-Akt axis regulates DC cytokine expression. Moreover, we will determine whether this regulatory pathway is essential for stimulating the adaptive immune response to the periodontal pathogen, P. gingivalis, and whether it plays a significant role in bacteria induced bone loss. To delete FOXO1 in DCs we will use the Cre-lox approach. We have already bred floxed FOXO1 mice with mice that express Cre recombinase under control of the CD11c promoter. DC isolated from the resulting experimental (CD11cCre+/FOXO1L/L) mice exhibit reduced cytokine expression stimulated by LPS compared to littermate control mice (CD11cCre-/FOXO1L/L). We will examine host-bacteria interactions in vivo by injecting P. gingivalis in the calvarial model. Because mice are naive to P. gingivalis we can examine the response when the adaptive immune response is not present and compare it to mice in which the adaptive immune response is activated by pre-immunization with P. gingivalis. By flow cytometry we will have a detailed analysis on the impact of FOXO1 deletion in generating a systemic and local adaptive immune response. The underlying calvarial bone will also be examined histologically to investigate the subsequent effect on osteoclastogenesis and bone resorption. The oral gavage model of applying P. gingivalis to the oral cavity will be studied in experimental (CD11cCre+/FOXO1L/L) and control mice (CD11cCre-/FOXO1L/L ) to determine whether FOXO1 deletion in DCs modulates the host response to P. gingivalis, osteoclastogenesis and periodontal disease progression. Experiments using the same two in vivo models will determine whether Akt is necessary to prevent a hyperinflammatory response in DC. These experiments will examine experimental (CD11cCre+/FOXO1L/L) and control (CD11cCre-/FOXO1L/L) mice.
In Aim 3 the mechanisms by which the FOXO1-Akt axis regulates selected target gene expression (IL-1, TNF, IL-6, and IL-12) will be examined in vitro.
The goal of the proposed studies is to investigate a potential etiologic mechanism for periodontal disease progression that involves the FOXO1-Akt axis in dendritic cells. Preliminary Data indicate that FOXO1 is needed for LPS induced cytokine expression in dendritic cells and that Akt1 fine tunes the response by regulating FOXO1. We propose that this has significant implications in periodontal disease and will determine how FOXO1 and Akt1 in dendritic cells may regulate and fine tune the adaptive immune response to P. gingivalis and P. gingivalis induced bone loss.
|Dong, Guangyu; Song, Liang; Tian, Chen et al. (2017) FOXO1 Regulates Bacteria-Induced Neutrophil Activity. Front Immunol 8:1088|
|Xiao, E; Mattos, Marcelo; Vieira, Gustavo Henrique Apolinário et al. (2017) Diabetes Enhances IL-17 Expression and Alters the Oral Microbiome to Increase Its Pathogenicity. Cell Host Microbe 22:120-128.e4|
|Graves, Dana T; Alshabab, Ahmed; Albiero, Mayra Laino et al. (2017) Osteocytes Play an Important Role in Experimental Periodontitis in Healthy and Diabetic Mice Through Expression of RANKL. J Clin Periodontol :|
|Tarapore, Rohinton S; Lim, Jason; Tian, Chen et al. (2016) NF-?B Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression. J Bone Miner Res 31:52-64|
|Souza, Joao Ac; Medeiros, Marcell C; Rocha, Fernanda Rg et al. (2016) Role of NOD2 and RIP2 in host-microbe interactions with Gram-negative bacteria: insights from the periodontal disease model. Innate Immun 22:598-611|
|Wu, Y; Dong, G; Xiao, W et al. (2016) Effect of Aging on Periodontal Inflammation, Microbial Colonization, and Disease Susceptibility. J Dent Res 95:460-6|
|Chaves de Souza, João Antônio; Frasnelli, Sabrina Cruz Tfaile; Curylofo-Zotti, Fabiana de Almeida et al. (2016) NOD1 in the modulation of host-microbe interactions and inflammatory bone resorption in the periodontal disease model. Immunology 149:374-385|
|Jiao, Hongli; Xiao, E; Graves, Dana T (2015) Diabetes and Its Effect on Bone and Fracture Healing. Curr Osteoporos Rep 13:327-35|
|Wang, Yu; Dong, Guangyu; Jeon, Hyeran Helen et al. (2015) FOXO1 mediates RANKL-induced osteoclast formation and activity. J Immunol 194:2878-87|
|Wu, Ying-Ying; Xiao, E; Graves, Dana T (2015) Diabetes mellitus related bone metabolism and periodontal disease. Int J Oral Sci 7:63-72|
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