Porphyromonas gingivalis triggers the shedding of inflammatory endothelial microvesicles that act as autocrine effectors of endothelial dysfunction

Abstract

A link between periodontitis and atherothrombosis has been highlighted. The aim of this study was to determine the influence of Porphyromonas gingivalis on endothelial microvesicles (EMV pg) shedding and their contribution to endothelial inflammation. Endothelial cells (EC) were infected with P. gingivalis (MOI = 100) for 24 h. EMV pg were isolated and their concentration was evaluated by prothrombinase assay. EMV pg were significantly increased in comparison with EMV ctrl shedded by unstimulated cells. While EMV ctrl from untreated EC had no effect, whereas, the proportion of apoptotic EC was increased by 30 nM EMV pg and viability was decreased down to 25%, a value elicited by P. gingivalis alone. Moreover, high concentration of EMV pg (30 nM) induced a pro-inflammatory and pro-oxidative cell response including up-regulation of TNF-α, IL-6 and IL-8 as well as an altered expression of iNOS and eNOS at both mRNA and protein level. An increase of VCAM-1 and ICAM-1 mRNA expression (4.5 folds and 3 folds respectively (p < 0.05 vs untreated) was also observed after EMV pg (30 nM) stimulation whereas P. gingivalis infection was less effective, suggesting a specific triggering by EMV pg. Kinasome analysis demonstrated the specific effect induced by EMV pg on main pro-inflammatory pathways including JNK/AKT and STAT. EMV pg are effective pro-inflammatory effectors that may have detrimental effect on vascular homeostasis and should be considered as potential autocrine and paracrine effectors involved in the link between periodontitis and atherothrombosis. Periodontitis is an infectious inflammatory disease associated with soft tissue inflammation and destruction of the tooth-supporting tissues characterized by increased periodontal pocket depth, gingival bleeding and clinical attachment loss. Such disease impairs oral health related quality of life and is considered the main cause of dental mobility and tooth loss 1. Periodontitis affects a large proportion of the worldwide population and prevalence of its severe forms is estimated to be around 11% with a peak incidence around 38 years of age 2. The development of periodontitis is associated with the establishment of a dysbiosis characterized by the predominance of anaerobic species, including Porphyromonas gingivalis (P. gingivalis), and an imbalanced host-immune response inducing periodontal tissue destruction 3. During the last decades, periodontal diseases were associated with various chronic diseases such as diabetes, rheumatoid arthritis, adverse pregnancy outcomes and cardiovascular diseases, suggesting a systemic impact 4-6 with an enhanced proportion of worsened cardiovascular outcomes 7-9. Indeed, patients with periodontitis are more prone to endothelial dysfunction, aneurysmal disease progression 10 , coronary artery narrowing, and an increased all-cause and cardio-vascular related mortality 11,12. Moreover, in a clinical trial, intensive periodontal

Membrane Microvesicles as Potential Vaccine Candidates

“…MVs play an essential role in cellular communication in physiological and pathological conditions, contributing to the pathogenesis of inflammation [ 88 , 89 , 90 , 91 , 92 , 93 , 94 ], coagulation [ 88 , 95 , 96 , 97 ], immunomodulation [ 93 ], regeneration [ 98 , 99 , 100 , 101 ] and tumorigenesis [ 76 , 102 ]. MV contribution to pathogenesis is often achieved through delivering cytokines, chemokines, mRNA and miRNA between cells [ 103 , 104 ].…”

Implication of Toll/IL-1 receptor domain containing adapters in Porphyromonas gingivalis-induced inflammation

“…[9][10][11][12] All these mechanisms are part of the bacterial strategy, aiming to escape the host immune response, thus contributing to the establishment of chronic inflammation and periodontal tissue destruction. 7,13 Nevertheless, P. gingivalis is also able to spread in other cell types, such as fibroblasts and endothelial cells (EC), 10,14 and, at distance, can be detected in several organs such as the liver or gut 15 and blood vessels. 16,17 Indeed, its implication in the development of systemic diseases, such as cardiovascular diseases and, particularly, atherothrombosis, is reported as several studies demonstrated that P. gingivalis is able to amplify and sustain inflammation, contributing to the development of atheromatous plaque in vitro and in vivo.…”

“…16,17 Indeed, its implication in the development of systemic diseases, such as cardiovascular diseases and, particularly, atherothrombosis, is reported as several studies demonstrated that P. gingivalis is able to amplify and sustain inflammation, contributing to the development of atheromatous plaque in vitro and in vivo. 14,15,[18][19][20] TLRs play a key role in the activation of the innate immune response against invading pathogens. 17,21 TLRs activate a molecular cascade that induces the secretion of inflammatory cytokines and adhesion molecules, such as IL-1b, IL-6, TNF-a, NF-jB, and other molecules involved in cell death.…”

Association between periodontitis and vascular endothelial function using noninvasive medical device—A pilot study

“…Porphyromonas gingivalis, a major periodontopathic pathogen, might be involved in exacerbation of cardiovascular disease (Bugueno, Zobairi El-Ghazouani, et al, 2020). A narrative review indicated that periodontal treatment may improve endothelial dysfunction, although the issue remains contentious (Parenti, Paccosi, Cairo, & Defraia, 2015).…”

“…A recent randomized clinical trial also revealed that periodontal treatment improved the endothelial function of patients following myocardial infarction (Lobo et al, 2020). Porphyromonas gingivalis , a major periodontopathic pathogen, might be involved in exacerbation of cardiovascular disease (Bugueno, Zobairi El‐Ghazouani, et al, 2020). A narrative review indicated that periodontal treatment may improve endothelial dysfunction, although the issue remains contentious (Parenti, Paccosi, Cairo, & Defraia, 2015).…”