The mechanisms of Porphyromonas gingivalis–derived outer membrane vesicles-induced neurotoxicity and microglia activation

IF 3.4 3区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE
Wei-Chun Chuang , Cheng-Ning Yang , Han-Wei Wang , Sze-Kwan Lin , Ching-Chu Yu , Jhe-Hao Syu , Chun-Pin Chiang , Young-Ji Shiao , Yi-Wen Chen
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引用次数: 0

Abstract

Background/purpose

Periodontitis is associated with various systemic diseases, potentially facilitated by the passage of Porphyromonas gingivalis outer membrane vesicles (Pg-OMVs). Several recent studies have suggested a connection between Pg-OMVs and neuroinflammation and neurodegeneration, but the precise causal relationship remains unclear. This study aimed to investigate the mechanisms underlying these associations using in vitro models.

Materials and methods

Isolated Pg-OMVs were characterized by morphology, size, and gingipain activity. We exposed SH-SY5Y neuroblastoma cells and BV-2 microglial cells to various concentrations of Pg-OMVs. Cell morphology, a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, an enzyme-linked immunosorbent assay, and Western blot analysis were used to evaluate the cellular mechanism underlying Pg-OMV-induced neurotoxicity in neuronal cells and inflammatory responses in microglial cells.

Results

Exposure to Pg-OMVs induced neurotoxicity in SH-SY5Y cells, as evidenced by cellular shrinkage, reduced viability, activation of apoptotic pathways, and diminished neuronal differentiation markers. Gingipain inhibition mitigated these effects, suggesting that gingipain mediates Pg-OMVs-induced neurotoxicity in SH-SY5Y cells. Our research on neuroinflammation suggests that upon endocytosis of Pg-OMVs by BV-2 cells, lipopolysaccharide (LPS) can modulate the production of inducible nitric oxide synthase and tumor necrosis factor-alpha by activating pathways that involve phosphorylated AKT and the phosphorylated JNK pathway.

Conclusion

Our study demonstrated that following the endocytosis of Pg-OMVs, gingipain can induce neurotoxicity in SH-SY5Y cells. Furthermore, the Pg-OMVs-associated LPS can trigger neuroinflammation via AKT and JNK signaling pathways in BV-2 cells.

牙龈卟啉单胞菌源性外膜囊泡诱导神经毒性和小胶质细胞活化的机制
背景/目的牙周炎与多种全身性疾病相关,牙龈卟啉单胞菌外膜小泡(Pg-OMVs)的通过可能会促进牙周炎的发生。最近的一些研究表明,牙龈卟啉单胞菌外膜囊泡与神经炎症和神经变性之间存在联系,但其确切的因果关系仍不清楚。本研究旨在利用体外模型研究这些关联的机制。材料与方法分离的Pg-OMVs具有形态、大小和gingipain活性等特征。我们将 SH-SY5Y 神经母细胞瘤细胞和 BV-2 小胶质细胞暴露于不同浓度的 Pg-OMVs 中。通过细胞形态学、3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑试验、酶联免疫吸附试验和 Western 印迹分析来评估 Pg-OMV 诱导神经细胞神经毒性和小胶质细胞炎症反应的细胞机制。结果暴露于Pg-OMV诱导的SH-SY5Y细胞神经毒性表现为细胞萎缩、存活率降低、凋亡通路激活和神经元分化标志物减少。抑制gingipain可减轻这些影响,这表明gingipain介导了Pg-OMV诱导的SH-SY5Y细胞神经毒性。我们对神经炎症的研究表明,BV-2细胞内吞Pg-OMVs后,脂多糖(LPS)可通过激活磷酸化AKT和磷酸化JNK通路,调节诱导型一氧化氮合酶和肿瘤坏死因子-α的产生。此外,与 Pg-OMVs 相关的 LPS 可通过 AKT 和 JNK 信号通路引发 BV-2 细胞的神经炎症。
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来源期刊
Journal of Dental Sciences
Journal of Dental Sciences 医学-牙科与口腔外科
CiteScore
5.10
自引率
14.30%
发文量
348
审稿时长
6 days
期刊介绍: he Journal of Dental Sciences (JDS), published quarterly, is the official and open access publication of the Association for Dental Sciences of the Republic of China (ADS-ROC). The precedent journal of the JDS is the Chinese Dental Journal (CDJ) which had already been covered by MEDLINE in 1988. As the CDJ continued to prove its importance in the region, the ADS-ROC decided to move to the international community by publishing an English journal. Hence, the birth of the JDS in 2006. The JDS is indexed in the SCI Expanded since 2008. It is also indexed in Scopus, and EMCare, ScienceDirect, SIIC Data Bases. The topics covered by the JDS include all fields of basic and clinical dentistry. Some manuscripts focusing on the study of certain endemic diseases such as dental caries and periodontal diseases in particular regions of any country as well as oral pre-cancers, oral cancers, and oral submucous fibrosis related to betel nut chewing habit are also considered for publication. Besides, the JDS also publishes articles about the efficacy of a new treatment modality on oral verrucous hyperplasia or early oral squamous cell carcinoma.
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