Department of Periodontics, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Disease, China Medical University, No. 117, Nanjing North Street, Heping District, Shenyang, China.
Department of Pediatric Dentistry, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Disease, China Medical University, No. 117, Nanjing North Street, Heping District, Shenyang, China.
Int J Oral Sci. 2023 Jan 12;15(1):3. doi: 10.1038/s41368-022-00215-y.
Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer's disease (AD). The blood-brain barrier (BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1 (Cav-1) expression was enhanced after P. gingivalis infection. Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain (RgpA) were detected. Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain containing 2a (Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurological impairments.
牙周感染引起的菌血症是牙周炎威胁全身健康的一个重要因素。牙龈卟啉单胞菌（P. gingivalis）的 DNA/毒力因子已在阿尔茨海默病（AD）患者的脑组织中发现。血脑屏障（BBB）对于防止有害物质进入脑组织至关重要。然而，牙龈卟啉单胞菌菌血症对 BBB 通透性的影响及其潜在机制尚不清楚。在本研究中，通过尾静脉每周三次向大鼠注射牙龈卟啉单胞菌，共 8 周，以诱导菌血症。还建立了感染牙龈卟啉单胞菌的体外 BBB 模型。我们发现，在有牙龈卟啉单胞菌菌血症和牙龈卟啉单胞菌的大鼠脑组织中，伊文思蓝染料的渗透和白蛋白蛋白沉积增加，并且牙龈卟啉单胞菌可以穿过体外 BBB 模型。在体内和体外，牙龈卟啉单胞菌感染后均检测到 BMEC 中的 caveolae。感染牙龈卟啉单胞菌后，Caveolin-1（Cav-1）的表达增强。下调 Cav-1 可挽救牙龈卟啉单胞菌增强的 BMEC 通透性。我们进一步发现，牙龈卟啉单胞菌的牙龈蛋白酶可与 Cav-1 共定位，并检测到 Cav-1 与 Arg 特异性牙龈蛋白酶（RgpA）之间的强氢键。此外，牙龈卟啉单胞菌显著抑制主要易化因子超家族域包含 2a（Mfsd2a）的表达。Mfsd2a 过表达逆转了牙龈卟啉单胞菌增加的 BMECs 通透性和 Cav-1 表达。这些结果表明，Mfsd2a/Cav-1 介导的转胞吞作用是调控牙龈卟啉单胞菌诱导的 BBB BMECs 通透性的关键途径，这可能有助于牙龈卟啉单胞菌/毒力因子进入和随后的神经损伤。
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