Exosomally Targeting microRNA23a Ameliorates Microvascular Endothelial Barrier Dysfunction Following Rickettsial Infection.
Exosomally Targeting microRNA23a Ameliorates Microvascular Endothelial Barrier Dysfunction Following Rickettsial Infection.
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DOI：
10.3389/fimmu.2022.904679
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
由立克次体（Rickettsia）（R）引起的斑点热群立克次体病是毁灭性的人类感染，其主要靶向微血管内皮细胞（EC），并可在脑和肺中诱导致命的EC屏障功能障碍。我们的前期研究表明，来源于立克次体感染的内皮细胞的外泌体（exosomes，Exos），即R-ECExos，可诱导紧密连接蛋白ZO-1的破坏和正常受体脑微血管内皮细胞（BMEC）屏障功能障碍。然而，根本的机制仍然难以捉摸。鉴于我们已经观察到microRNA 23 a（miR 23 a）（内皮ZO-1 mRNA的负调节剂）被选择性地分选到R-ECExos中，本研究的目的是表征由R-ECExos递送的外泌体miR 23 a在正常受体BMEC中的潜在功能作用。我们证明了EC衍生的Exos（ECExos）具有在RNA酶丰富的环境中将寡核苷酸RNA递送至正常受体BMEC的能力。ECExos中的miR 23 a损害正常受体BMEC屏障功能，直接靶向TJ蛋白ZO-1 mRNA。在使用传统体外模型和新型单活细胞生物力学测定的单独研究中，我们的研究小组证明，富含miR 23 a反义寡核苷酸的ECExos改善了R-ECExo引起的受体BMEC功能障碍，并与ZO-1的稳定相关。剂量依赖性方式。这些结果表明，基于Exo的治疗可能被证明是在细菌感染和伴随炎症期间改善血管屏障功能的有前景的策略。
Spotted fever group rickettsioses caused by Rickettsia (R) are devastating human infections, which mainly target microvascular endothelial cells (ECs) and can induce lethal EC barrier dysfunction in the brain and lungs. Our previous evidence reveals that exosomes (Exos) derived from rickettsial-infected ECs, namely R-ECExos, can induce disruption of the tight junctional (TJ) protein ZO-1 and barrier dysfunction of human normal recipient brain microvascular endothelial cells (BMECs). However, the underlying mechanism remains elusive. Given that we have observed that microRNA23a (miR23a), a negative regulator of endothelial ZO-1 mRNA, is selectively sorted into R-ECExos, the aim of the present study was to characterize the potential functional role of exosomal miR23a delivered by R-ECExos in normal recipient BMECs. We demonstrated that EC-derived Exos (ECExos) have the capacity to deliver oligonucleotide RNAs to normal recipient BMECs in an RNase-abundant environment. miR23a in ECExos impairs normal recipient BMEC barrier function, directly targeting TJ protein ZO-1 mRNAs. In separate studies using a traditional in vitro model and a novel single living-cell biomechanical assay, our group demonstrated that miR23a anti-sense oligonucleotide-enriched ECExos ameliorate R-ECExo-provoked recipient BMEC dysfunction in association with stabilization of ZO-1 in a dose-dependent manner. These results suggest that Exo-based therapy could potentially prove to be a promising strategy to improve vascular barrier function during bacterial infection and concomitant inflammation.
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影响因子：
3.8
作者：
Gong B;Ma L;Liu Y;Gong Q;Shelite T;Bouyer D;Boor PJ;Lee YS;Oberhauser A
通讯作者：
Oberhauser A
影响因子：
16
作者：
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影响因子：
3.7
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通讯作者：
Walker DH
影响因子：
4.7
作者：
Jones LB;Bell CR;Bibb KE;Gu L;Coats MT;Matthews QL
通讯作者：
Matthews QL
影响因子：
4
作者：
Fitzner, Dirk;Schnaars, Mareike;Simons, Mikael
通讯作者：
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