Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
Microbiol Spectr. 2023 Jun 15;11(3):e0476922. doi: 10.1128/spectrum.04769-22. Epub 2023 May 18.
Porphyromonas gingivalis is an important periodontal pathogen that can cause vascular injury and invade local tissues through the blood circulation, and its ability to evade leukocyte killing is critical to its distal colonization and survival. Transendothelial migration (TEM) is a series of that enable leukocytes to squeeze through endothelial barriers and migrate into local tissues to perform immune functions. Several studies have shown that P. gingivalis-mediated endothelial damage initiates a series of proinflammatory signals that promote leukocyte adhesion. However, whether P. gingivalis is involved in TEM and thus influences immune cell recruitment remains unknown. In our study, we found that P. gingivalis gingipains could increase vascular permeability and promote Escherichia coli penetration by downregulating platelet/endothelial cell adhesion molecule 1 (PECAM-1) expression . Furthermore, we demonstrated that although P. gingivalis infection promoted monocyte adhesion, the TEM capacity of monocytes was substantially impaired, which might be due to the reduced CD99 and CD99L2 expression on gingipain-stimulated endothelial cells and leukocytes. Mechanistically, gingipains mediate CD99 and CD99L2 downregulation, possibly through the inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway. In addition, our model confirmed the role of P. gingivalis in promoting vascular permeability and bacterial colonization in the liver, kidney, spleen, and lung and in downregulating PECAM-1, CD99, and CD99L2 expression in endothelial cells and leukocytes. 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. A similar phenomenon was also observed in a mouse model. These findings established P. gingivalis gingipains as the key virulence factor in modulating the permeability of the vascular barrier and TEM processes, which may provide a new rationale for the distal colonization of P. gingivalis and its associated systemic diseases.
牙龈卟啉单胞菌是一种重要的牙周病原体，它可以通过血液循环引起血管损伤并侵犯局部组织，其逃避白细胞杀伤的能力对其远端定植和存活至关重要。跨内皮迁移（TEM）是一系列使白细胞能够挤过内皮屏障并迁移到局部组织中执行免疫功能的过程。有几项研究表明，牙龈卟啉单胞菌介导的内皮损伤会引发一系列促炎信号，促进白细胞黏附。然而，牙龈卟啉单胞菌是否参与 TEM 从而影响免疫细胞募集仍不清楚。在我们的研究中，我们发现牙龈卟啉单胞菌的牙龈蛋白酶可以通过下调血小板/内皮细胞黏附分子 1（PECAM-1）的表达来增加血管通透性并促进大肠杆菌渗透。此外，我们证明，尽管牙龈卟啉单胞菌感染促进单核细胞黏附，但单核细胞的 TEM 能力显著受损，这可能是由于牙龈蛋白酶刺激的内皮细胞和白细胞上 CD99 和 CD99L2 的表达减少。在机制上，牙龈蛋白酶介导 CD99 和 CD99L2 的下调，可能是通过抑制磷酸肌醇 3-激酶（PI3K）/Akt 途径。此外，我们的模型证实了牙龈卟啉单胞菌在促进肝脏、肾脏、脾脏和肺部的血管通透性和细菌定植以及下调内皮细胞和白细胞上的 PECAM-1、CD99 和 CD99L2 表达中的作用。牙龈卟啉单胞菌与多种全身性疾病有关，并定植在体内的远端部位。在这里，我们发现牙龈卟啉单胞菌的牙龈蛋白酶降解 PECAM-1 以促进细菌渗透，同时降低白细胞 TEM 能力。在小鼠模型中也观察到类似的现象。这些发现确立了牙龈卟啉单胞菌的牙龈蛋白酶作为调节血管屏障通透性和 TEM 过程的关键毒力因子，这可能为牙龈卟啉单胞菌的远端定植及其相关全身性疾病提供新的依据。
