Porphyromonas gingivalis Gingipains Destroy the Vascular Barrier and Reduce CD99 and CD99L2 Expression To Regulate Transendothelial Migration

Zou, Zhaolei; Fang, Juan; Ma, Wanting; Guo, Junyi; Shan, Zhongyan; Ma, Dawei; Hu, Qian-Nan; Wen, Liling; Wang, Zhi

doi:10.1128/spectrum.04769-22

Cited by 4 publications

(2 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This disruption in BBB integrity is caused by the downregulation or derangement of brain microvascular endothelial cells (BMECs) tight junction proteins. Gingipains are potent proteolytic enzymes produced by Pg that degrade tight junction proteins of human endothelial cells [3,4]. In addition, gingipains were detected in brain tissue samples of AD patients [6].…”

Section: Discussionmentioning

confidence: 99%

“…Periodontitis (PD) is a chronic inflammatory degenerative bone disease affecting more than 50% of the adult US population, with oral infectious etiology and increased prevalence in advanced age [2]. A role for periodontitis (PD) in the pathogenesis of AD has recently been proposed by several studies [3][4][5][6][7][8][9][10][11][12][13]. In addition, gingipains, proteolytic enzymes of the keystone oral pathogen Porphyromonas gingivalis (Pg), have been detected in the brains of AD patients postmortem [6].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier

Elashiry,

Carroll,

Yuan

et al. 2024

IJMS

View full text Add to dashboard Cite

Porphyromonas gingivalis (Pg) and its gingipain proteases contribute to Alzheimer’s disease (AD) pathogenesis through yet unclear mechanisms. Cellular secretion of small extracellular vesicles or exosomes (EXO) increases with aging as part of the senescence-associated secretory phenotype (SASP). We have shown that EXO isolated from Pg-infected dendritic cells contain gingipains and other Pg antigens and transmit senescence to bystander gingival cells, inducing alveolar bone loss in mice in vivo. Here, EXO were isolated from the gingiva of mice and humans with/without periodontitis (PD) to determine their ability to penetrate the blood–brain barrier (BBB) in vitro and in vivo. PD was induced by Pg oral gavage for 6 weeks in C57B6 mice. EXO isolated from the gingiva or brain of donor Pg-infected (PD EXO) or control animals (Con EXO) were characterized by NTA, Western blot, and TEM. Gingival PD EXO or Con EXO were labeled and injected into the gingiva of uninfected WT mouse model. EXO biodistribution in brains was tracked by an in vivo imaging system (IVIS) and confocal microscopy. The effect of human PD EXO on BBB integrity and permeability was examined using TEER and FITC dextran assays in a human in vitro 3D model of the BBB. Pg antigens (RGP and Mfa-1) were detected in EXO derived from gingival and brain tissues of donor Pg-infected mice. Orally injected PD EXO from donor mice penetrated the brains of recipient uninfected mice and colocalized with hippocampal microglial cells. IL-1β and IL-6 were expressed in human PD EXO and not in Con EXO. Human PD EXO promoted BBB permeability and penetrated the BBB in vitro. This is the first demonstration that microbial-induced EXO in the oral cavity can disseminate, cross the BBB, and may contribute to AD pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier

Elashiry,

Carroll,

Yuan

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

From gingiva to multiple organs in mice: The trace of Porphyromonas gingivalis via in vivo imaging

Cheng,

Zou,

et al. 2024

Journal of Dental Sciences

View full text Add to dashboard Cite

Porphyromonas gingivalis outer membrane vesicles increase vascular permeability by inducing stress fiber formation and degrading vascular endothelial‐cadherin in endothelial cells

Mekata,

Yoshida,

Takai

et al. 2024

The FEBS Journal

View full text Add to dashboard Cite

Porphyromonas gingivalis (Pg) is a keystone bacterium associated with systemic diseases, such as diabetes mellitus and Alzheimer's disease. Outer membrane vesicles (OMVs) released from Pg have been implicated in systemic diseases by delivering Pg virulence factors to host cells in distant organs and inducing cellular dysfunction. Pg OMVs also have the potential to enter distant organs via the bloodstream. However, the effects of Pg OMVs on the vascular function are poorly understood. Here, we showed that Pg OMVs increase vascular permeability by promoting stress fiber formation and lysosome/endosome‐mediated vascular endothelial‐cadherin (VEc) degradation in human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs). F‐actin, visualized via fluorescein isothiocyanate‐phalloidin, became thicker and longer, leading to the formation of radical stress fibers in response to Pg OMVs in HUVECs and HPMECs. Western blotting and quantitative real‐time polymerase chain reaction analyses revealed that Pg OMVs decreased VEc protein levels in a gene‐independent manner. Pg OMVs enhanced vesicular VEc accumulation in the cytoplasm around lysosome‐associated membrane protein 1‐positive structures during pretreatment with the lysosomal inhibitor chloroquine. This suggests that Pg OMVs decrease VEc protein levels by accelerating their internalization and degradation via lysosomes and endosomes. A27632 inhibition of Rho kinases impaired the Pg OMV‐induced stress fiber formation and VEc degradation, resulting in the recovery of hyperpermeability. These findings provide new insights into the pathogenesis of systemic diseases that are associated with periodontal diseases.

show abstract

Porphyromonas gingivalis Gingipains Destroy the Vascular Barrier and Reduce CD99 and CD99L2 Expression To Regulate Transendothelial Migration

Abstract: P. gingivalis is associated with a variety of systemic diseases and colonizes in distal locations in the body. Here, we found that P. gingivalis gingipains degrade PECAM-1 to promote bacterial penetration while simultaneously reducing leukocyte TEM capacity.

Cited by 4 publications

References 51 publications

Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier

Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier

From gingiva to multiple organs in mice: The trace of Porphyromonas gingivalis via in vivo imaging

Porphyromonas gingivalis outer membrane vesicles increase vascular permeability by inducing stress fiber formation and degrading vascular endothelial‐cadherin in endothelial cells

Contact Info

Product

Resources

About