Introduction

Growing evidence has shown the correlation between periodontitis and atherosclerosis, while our knowledge on the pathogenesis of periodontitis-promoting atherosclerosis is far from sufficient.

Objectives

Illuminate the pathogenic effects of Fusobacterium nucleatum (F. nucleatum) on intracellular lipid deposition in THP-1-derived macrophages and elucidate the underlying pathogenic mechanism of how F. nucleatum promoting atherosclerosis.

Methods and results

F. nucleatum was frequently detected in different kinds of atherosclerotic plaques and its abundance was positively correlated with the proportion of macrophages. In vitro assays showed F. nucleatum could adhere to and invade THP-1 cells, and survive continuously in macrophages for 24 h. F. nucleatum stimulation alone could significantly promote cellular inflammation, lipid uptake and inhibit lipid outflow. The dynamic gene expression of THP-1 cells demonstrated that F. nucleatum could time-serially induce the over-expression of multiple inflammatory related genes and activate NF-κB, MAPK and PI3K-AKT signaling pathways. The exoprotein of F. nucleatum, D-galactose-binding protein (Gbp), acted as one of the main pathogenic proteins to interact with the Cyclophilin A (CypA) of THP-1 cells and induced the activation of the NF- κB, MAPK and PI3K-AKT signaling pathways. Furthermore, use of six candidate drugs targeting to the key proteins in NF- κB, MAPK and PI3K-AKT pathways could dramatically decrease F. nucleatum induced inflammation and lipid deposition in THP-1 cells.

Conclusions

This study suggests that the periodontal pathogen F. nucleatum can activate macrophage PI3K-AKT/MAPK/NF-κB signal pathways, promotes inflammation, enhances cholesterol uptake, reduces lipid excretion, and promotes lipid deposition, which may be one of its main strategies promoting the development of atherosclerosis.

中文翻译：

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具核梭杆菌的胞外蛋白 Gbp 通过与 CypA 结合并激活 PI3K-AKT/MAPK/NF-κB 通路促进 THP-1 细胞脂质沉积

介绍

越来越多的证据表明牙周炎与动脉粥样硬化之间存在相关性，而我们对牙周炎促进动脉粥样硬化的发病机制的了解还远远不够。

目标

阐明具核梭杆菌( F. nucleatum ) 对 THP-1 衍生巨噬细胞细胞内脂质沉积的致病作用，阐明具核梭杆菌促进动脉粥样硬化的潜在致病机制。

方法和结果

F. nucleatum在不同类型的动脉粥样硬化斑块中频繁检测到，其丰度与巨噬细胞的比例呈正相关。体外实验表明具核梭杆菌可以粘附并侵入THP-1细胞，并在巨噬细胞中连续存活24小时。单独的F. nucleatum刺激可以显着促进细胞炎症、脂质摄取和抑制脂质流出。THP-1 细胞的动态基因表达表明具核梭杆菌可以时间序列诱导多个炎症相关基因的过度表达并激活 NF-κB、MAPK 和 PI3K-AKT 信号通路。F. nucleatum的胞外蛋白, D-半乳糖结合蛋白 (Gbp), 作为主要致病蛋白之一与 THP-1 细胞的亲环素 A (CypA) 相互作用并诱导 NF-κB、MAPK 和 PI3K-AKT 信号通路的激活. 此外，使用六种靶向 NF-κB、MAPK 和 PI3K-AKT 通路中关键蛋白的候选药物可以显着减少THP-1 细胞中F. nucleatum诱导的炎症和脂质沉积。

结论

本研究表明，牙周病原体具核梭杆菌可激活巨噬细胞 PI3K-AKT/MAPK/NF-κB 信号通路，促进炎症反应，增强胆固醇摄取，减少脂质排泄，促进脂质沉积，这可能是其促进炎症的主要策略之一动脉粥样硬化的发展。