Abstract
There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr°) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls. This increase was entirely CD36/SR-B2-dependent, as there was no significant change in lesion burden between infected and uninfected Ldlr° mice. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1ß generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release. In the vessel wall, macrophages encountering systemic release of IL1ß, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1ß, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics.
Highlights
In the US, greater than 20% of adults aged 35–64 have moderate to severe periodontal disease (PD), and this is likely underestimated [1,2,3]
Atherosclerosis lesion burden is increased in Porphyromonas gingivalis (Pg) infected Ldlr° mice and the increase is mediated by CD36/scavenger receptor-B2 (SR-B2)
There were no differences in lesion area between male Western diet (WD) fed Ldlr° and Cd36°/Ldlr° mice (Fig 2A, 7.97% ± 1.06 vs 7.63% ± 1.3), or female WD fed Ldlr° and Cd36°/Ldlr° mice (Fig 2B, 5.6% ± 0.8 vs 6.72% ± 1.37) which confirms our previous study showing that atherosclerosis in this model is CD36/SR-B2 independent [33]
Summary
In the US, greater than 20% of adults aged 35–64 have moderate to severe periodontal disease (PD), and this is likely underestimated [1,2,3]. An important question has emerged: how is a localized and largely isolated oral infection transduced to the aortic vasculature to promote atherosclerosis? While there has been substantive progress in reducing risk associated with dyslipidemia in treatment of atherosclerosis, there has been less therapeutic focus on chronic infectious diseases such as PD [13]. The prevalence of PD, its association with diabetes and obesity, which are increasing rapidly globally, and its increased severity in the elderly population, underscore the necessity for research in this area and the significance of the problem [14,15,16,17]
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