[Show abstract][Hide abstract] ABSTRACT: The low-grade oral infection chronic periodontitis (CP) has been implicated in coronary artery disease risk, but the mechanisms are unclear. In this study, a pathophysiological role for blood dendritic cells (DCs) in systemic dissemination of oral mucosal pathogens to atherosclerotic plaques was investigated in humans. The frequency and microbiome of CD19(-)BDCA-1(+)DC-SIGN(+) blood myeloid DCs (mDCs) were analyzed in CP subjects with or without existing acute coronary syndrome and in healthy controls. FACS analysis revealed a significant increase in blood mDCs in the following order: healthy controls < CP < acute coronary syndrome/CP. Analysis of the blood mDC microbiome by 16S rDNA sequencing showed Porphyromonas gingivalis and other species, including (cultivable) Burkholderia cepacia. The mDC carriage rate with P. gingivalis correlated with oral carriage rate and with serologic exposure to P. gingivalis in CP subjects. Intervention (local debridement) to elicit a bacteremia increased the mDC carriage rate and frequency in vivo. In vitro studies established that P. gingivalis enhanced by 28% the differentiation of monocytes into immature mDCs; moreover, mDCs secreted high levels of matrix metalloproteinase-9 and upregulated C1q, heat shock protein 60, heat shock protein 70, CCR2, and CXCL16 transcripts in response to P. gingivalis in a fimbriae-dependent manner. Moreover, the survival of the anaerobe P. gingivalis under aerobic conditions was enhanced when within mDCs. Immunofluorescence analysis of oral mucosa and atherosclerotic plaques demonstrate infiltration with mDCs, colocalized with P. gingivalis. Our results suggest a role for blood mDCs in harboring and disseminating pathogens from oral mucosa to atherosclerosis plaques, which may provide key signals for mDC differentiation and atherogenic conversion.
The Journal of Immunology 08/2012; 189(6):3178-87. DOI:10.4049/jimmunol.1201053 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An estimated 80 million U.S. adults have one or more types of cardiovascular diseases (CVD)with the total cost to the U.S. for 2009 estimated to be $475.3 billion. Atherosclerosis (ATH) is the single most important contributor to CVD; however, only 50% of ATH patients have currently identified risk factors. Chronic periodontitis (CP), a common inflammatory disease, is linked to an increased CVD risk. Dendritic cells (DCs) which infiltrate arterial walls and destabilize atherosclerotic plaques, have been implicated in CVD. While the source of atherogenic DCs is presently unclear, we propose that dermal DCs from peripheral inflamed sites, such as CP tissues are a source. Objectives: we therefore designed a clinical study to elicit, quantitate and isolate DCs in the peripheral blood of otherwise healthy CP patients. Methods: ten patients with CP were consented according to IRB standards and enrolled in the study. Peripheral blood collected at baseline and 24 hrs after mechanical debridement (MD) was used to identify and sort blood DCs. After PBMC separation, DCs were labeled with DC-SIGN-APC and BDCA-1-PE and quantitated by FACS analysis. Results: we found that after MD there was a 5-6% increase in the numbers of blood DCs in this patient population. Conclusion: this increase in the blood may represent mobilization of DCs from bone marrow stores, as well as from CP tissues. We are presently analyzing the DC transcriptome of sorted DCs to identify markers of atherogenesis. 1K23DE018187-01