The exoprotein Gbp of Fusobacterium nucleatum promotes THP-1 cell lipid deposition by binding to CypA and activating PI3K-AKT/MAPK/NF-κB pathways

• Published in: Journal of advanced research 2024-03, Vol.57, p.93-105
• Main Authors: Shen, Song, Sun, Tianyong, Ding, Xiangjiu, Gu, Xiufeng, Wang, Yushang, Ma, Xiaomei, Li, Zixuan, Gao, Haiting, Ge, Shaohua, Feng, Qiang
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Calcium-Binding Proteins; Cyclophilin A; CypA; Drug repositioning; Fusobacterium nucleatum; Gbp; Humans; Inflammation; Lipid deposition; Lipids; Monosaccharide Transport Proteins; NF-kappa B; Original; Periodontitis; Periplasmic Binding Proteins; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA-seq; THP-1 Cells
• ISSN: 2090-1232; 2090-1224; 2090-1224
• DOI: 10.1016/j.jare.2023.04.007

[Display omitted] •F. nucleatum was prevalent in diffuse intimal thickening as well as in plaque tissues;•F. nucleatum participated in the foaming process of THP-1 cells by activating MAPK, PI3K-AKT, and NF-κB signaling cascades;•The exoprotein of F. nucleatum, Gbp, promoted foam cell formation by interacting with CypA and CD147 and activating the PI3K-AKT, MAPK and NF-κB signaling pathways;•Drug candidates targeting PI3K-AKT, MAPK and NF-κB signaling pathways could dramatically attenuate F. nucleatum induced macrophage foaming. Growing evidence has shown the correlation between periodontitis and atherosclerosis, while our knowledge on the pathogenesis of periodontitis-promoting atherosclerosis is far from sufficient. 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. 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. 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.