Interactions of oral pathogens with toll-like receptors: possible role in atherosclerosis.
Toll-like receptors (TLR) function as important signal transducers that mediate innate immune and inflammatory responses to pathogens through pattern recognition of virulence molecules. Although TLRs mediate protection against infection, it is also likely that they may have a pathophysiologic role in certain inflammatory diseases, such as atherosclerosis. In atherosclerotic lesions, endothelial cells and macrophages have been shown to upregulate TLR expression and may respond to TLR agonists of microbial origin, resulting in detrimental inflammatory reactions. Some of these potential TLR-activating virulence factors may be of oral origin. The detection in atherosclerotic plaques of DNA specific for Porphyromonas gingivalis and other periodontal pathogens suggests that these pathogens disseminate into the systemic circulation and localize in atheromas. The potential of periodontal and some other oral pathogens to activate TLRs in vivo is suggested by findings from cell culture experiments on interactions of selected virulence protein adhesins with TLRs and their coreceptors. Specifically, we have shown that proinflammatory cytokine induction by P. gingivalis fimbriae was inhibited by monoclonal antibodies to TLR2, TLR4, CD14, and beta2 integrins, but not by immunoglobulin isotype controls. Cytokine induction by Bacteroides forsythus protein A depended heavily on CD14 and TLR2. We also found that the ability of Streptococcus mutans protein AgI/II to stimulate cytokine release was partially dependent on CD14 and TLR4. Moreover, P. gingivalis fimbriae induced TLR-dependent activation of nuclear factor-kappaB and upregulation of costimulatory molecules in monocytic cells. These proinflammatory activities have been implicated in the pathogenesis of periodontitis, and similar inflammatory mechanisms could potentially operate in atherosclerosis. Studies by other groups have shown that P. gingivalis is capable of stimulating low-density lipoprotein oxidation, foam cell formation, and rupture of atherosclerotic plaque through induction of matrix metalloproteinases. Interestingly, at least some of these activities can be induced by TLR agonists (lipopolysaccharide and heat-shock protein-60) from Chlamydia pneumoniae, a major risk factor in atherosclerosis. Future research in animal models and in vitro cellular systems with defined mutations in TLRs may implicate TLR participation in oral pathogen-mediated atherosclerotic processes, thereby providing a mechanistic basis for the epidemiological findings linking oral pathogens to atherosclerotic disease.
Hajishengallis
George
G
Department of Oral Biology, University at Buffalo, Buffalo, New York, USA. gh6@acsu.buffalo.edu
Sharma
Ashu
A
Russell
Michael W
MW
Genco
Robert J
RJ
D001161:Arteriosclerosis / Q000378:metabolism / Q000382:microbiology*; D001421:Bacteria, Anaerobic / Q000472:pathogenicity / Q000502:physiology*; D001439:Bacteroides / Q000472:pathogenicity / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D036781:Fimbriae Proteins / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D010510:Periodontal Diseases / Q000382:microbiology*; D016966:Porphyromonas gingivalis / Q000472:pathogenicity / Q000502:physiology; D011956:Receptors, Cell Surface / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D013295:Streptococcus mutans / Q000472:pathogenicity / Q000502:physiology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D037521:Virulence Factors / Q000502:physiology
D016207:Cytokines; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D037521:Virulence Factors; D036781:Fimbriae Proteins