Delivery of Periodontopathogenic Extracellular Vesicles to Brain Monocytes and Microglial IL-6 Promotion by RNA Cargo.
Delivery of Periodontopathogenic Extracellular Vesicles to Brain Monocytes and Microglial IL-6 Promotion by RNA Cargo.
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DOI：
10.3389/fmolb.2020.596366
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发表时间：
2020
影响因子：
5
通讯作者：
Lee HJ
中科院分区：
文献类型：
--
作者：
Ha JY;Choi SY;Lee JH;Hong SH;Lee HJ
革兰氏阴性细菌细胞外囊泡（EV），也称为外膜囊泡（OMV），由细菌细胞分泌，并且由于其在细胞间通讯中的作用而引起研究关注。在OMV分泌期间，多种货物如胞外RNA（exRNA）被加载到OMV中。已经在几种疾病中鉴定了来自一系列细菌的exRNA的参与，然而，它们的作用机制尚未阐明。我们最近已经证明，牙周病病原体伴放线菌聚集杆菌分泌的OMV可以穿过血脑屏障（BBB），其exRNA货物可以促进脑中促炎细胞因子的分泌。然而，目前尚不清楚大脑免疫细胞是否真的可以在适当的免疫反应中吸收源自大脑外部的细菌OMV。在本研究中，使用单核细胞特异性活CX 3CR 1-GFP小鼠，我们观察了OMV共定位的脑膜巨噬细胞和小胶质细胞，其中细菌OMV已加载并通过尾静脉静脉注射。我们的研究结果表明，脑膜巨噬细胞吸收血脑屏障交叉OMV早于皮质小胶质细胞。还在OMV处理后观察BV 2细胞（鼠小胶质细胞系）和exRNA，并观察它们的促炎细胞因子水平。白细胞介素（IL）-6和NF-κB在A.伴随放线菌exRNA的表达，而不受OMV DNA货物的影响。总之，这些发现表明OMV可以成功地将exRNA递送到脑单核细胞/小胶质细胞中并引起神经炎症，这暗示了神经炎症疾病中的新致病机制。
Gram-negative bacterial extracellular vesicles (EVs), also known as outer membrane vesicles (OMVs), are secreted from bacterial cells and have attracted research attention due to their role in cell-to-cell communication. During OMV secretion, a variety of cargo such as extracellular RNA (exRNA) is loaded into the OMV. The involvement of exRNAs from a range of bacteria has been identified in several diseases, however, their mechanism of action has not been elucidated. We have recently demonstrated that OMVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans can cross the blood–brain barrier (BBB) and that its exRNA cargo could promote the secretion of proinflammatory cytokines in the brain. However, it was unclear whether the brain immune cells could actually take up bacterial OMVs, which originate outside of the brain, in an appropriate immune response. In the present study, using monocyte-specific live CX3CR1-GFP mice, we visualized OMV-colocalized meningeal macrophages and microglial cells into which bacterial OMVs had been loaded and intravenously injected through tail veins. Our results suggested that meningeal macrophages uptake BBB-crossed OMVs earlier than do cortex microglia. BV2 cells (a murine microglia cell line) and exRNAs were also visualized after OMV treatment and their proinflammatory cytokine levels were observed. Interleukin (IL)-6 and NF-κB of BV2 cells were activated by A. actinomycetemcomitans exRNAs but not by OMV DNA cargo. Altogether, these findings indicate that OMVs can successfully deliver exRNAs into brain monocyte/microglial cells and cause neuroinflammation, implicating a novel pathogenic mechanism in neuroinflammatory diseases.