The Effects of Porphyromonas gingivalis on Atherosclerosis-Related Cells

Abstract

Atherosclerosis (AS), one of the most common types of cardiovascular disease, has initially been attributed to the accumulation of fats and fibrous materials. However, more and more researchers regarded it as a chronic inflammatory disease nowadays. Infective disease, such as periodontitis, is related to the risk of atherosclerosis. Porphyromonas gingivalis (P. gingivalis), one of the most common bacteria in stomatology, is usually discovered in atherosclerotic plaque in patients. Furthermore, it was reported that P. gingivalis can promote the progression of atherosclerosis. Elucidating the underlying mechanisms of P. gingivalis in atherosclerosis attracted attention, which is thought to be crucial to the therapy of atherosclerosis. Nevertheless, the pathogenesis of atherosclerosis is much complicated, and many kinds of cells participate in it. By summarizing existing studies, we find that P. gingivalis can influence the function of many cells in atherosclerosis. It can induce the dysfunction of endothelium, promote the formation of foam cells as well as the proliferation and calcification of vascular smooth muscle cells, and lead to the imbalance of regulatory T cells (Tregs) and T helper (Th) cells, ultimately promoting the occurrence and development of atherosclerosis. This article summarizes the specific mechanism of atherosclerosis caused by P. gingivalis. It sorts out the interaction between P. gingivalis and AS-related cells, which provides a new perspective for us to prevent or slow down the occurrence and development of AS by inhibiting periodontal pathogens.

Keywords: Porphyromonas gingivalis; T cell; atherosclerosis; endothelial dysfunction; foam cell.

Figure 1

Characteristic of P. gingivalis. (1) As the most common periodontal pathogen, P. gingivalis is composed of cell membrane and genetic material. The outer layer of the cell membrane has a large number of fimbriae, proteins, and channels. (2) The pathogenicity of P. gingivalis mainly comes from its own structural components (lipopolysaccharide, fimbriae, and heat shock proteins) and secretory components (gingipains and outer membrane vesicles, OMVs). (3) OMVs have a double-layer spherical membrane and contain a lot of pathogenic factors with high concentration.

Figure 2

Pathogenesis of atherosclerosis (AS). (1) As the picture shows, AS occurs in the intima, where endothelial cell damage and monocyte migration and adhesion occur. (2) After the monocytes enter the inner membrane, they differentiate into macrophages and increase the uptake of oxLDL to become foam cells. (3) Outside the intima, the media contains vascular smooth muscle cells, which proliferate and migrate to the intima and then differentiate into vascular smooth muscle cell-derived foam cells.

Figure 3

Molecular cascades activated by P. gingivalis in endothelial cells (ECs). (1) TLR is believed to mediate the recognition of P. gingivalis. P. gingivalis promotes EC oxidative stress through the TLRs–NF-κB signal axis and NLRP3 inflammasomes. P. gingivalis leads to nitrifying stress and impaired endothelial function, with upregulating iNOS, downregulating eNOS, and regulating the release of NO in EC (86), which is associated with the change of the GSK-3β/BH4/eNOS/Nrf2 pathway. (2) P. gingivalis gingipains induced endothelial cell (EC) apoptosis by activating caspase-3,8,9, and its gingipains can also induce EC apoptosis mainly through inducing the cleavage of PARP and Topo I. (3) P. gingivalis lipopolysaccharide promoted EndMT through the regulation of p38, Erk1/2, and p65. (4) P. gingivalis enhanced monocyte migration with an increased expression of MCP-1, ICAM-1, IL-8, P-selectin, and E-selectin in ECs. (5) Gingipain destroyed the endothelial cell–cell junction through inducing the cleavage of VE-cadherin, N-cadherin, PECAM-1, and integrin β1.

Figure 4

Molecular cascades activated by P. gingivalis in macrophages. (1) P. gingivalis recognizes TLR2, binds to CR3, and enters macrophages. The intracellular P. gingivalis stimulates TLR2 through its surface fimbriae, thereby inducing the high-affinity conformation of CR3, which is conducive to the uptake of more P. gingivalis by macrophages. (2) SR-A and CD36, as the clearance receptors of macrophages, mediate the internalization of oxLDL, thereby promoting the accumulation of intracellular cholesterol. In contrast, SR-BI and ABCA1/ABCG1 are responsible for cholesterol efflux. P. gingivalis lipopolysaccharide increased the expression of CD36 through the c-Jun-AP-1 pathway and promoted cholesterol accumulation in macrophages. (3) P. gingivalis outer membrane vesicles stimulated the macrophages to produce matrix metalloproteinases capable of cleaving the apoB-100 of low-density lipoprotein (LDL) particles to increase the modification of LDL. (4) P. gingivalis promoted the production of pro-inflammatory cytokines, like IL-1, IL-18, IL-6, and TNF-α in macrophages, with the activation of NLRP3 inflammasomes.

Figure 5

P. gingivalis infection cause Th17/Treg imbalance. (1) In the process of atherosclerosis, P. gingivalis infection increased the number and response of Th17, inhibited Tregs with regulatory effects, and cause Th17/Treg imbalance. (2) P. gingivalis reduced the number and inhibited the regulatory function of Tregs with the downregulation of IL-10 and TGF-β1. P. gingivalis promoted a Th17/IL-17 response resulting in increased TNF-α, IL-1β, IL-6, and IL-17 production by T cells, which may be mediated by TLR2/TLR4 signaling.