Extracellular RNA promotes leukocyte recruitment in the vascular system by mobilising proinflammatory cytokines
Extracellular RNA promotes leukocyte recruitment in the vascular system by mobilising proinflammatory cytokines
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DOI：
10.1160/th12-03-0186
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发表时间：
2012-10-01
影响因子：
6.7
通讯作者：
Deindl, Elisabeth
中科院分区：
文献类型：
--
作者：
Fischer, Silvia;Grantzow, Tobias;Deindl, Elisabeth
细胞外 RNA (eRNA) 在损伤或血管疾病的情况下从细胞中释放出来，作为有效的促血栓因子，促进与体内水肿形成相关的血管通透性过高。在这项研究中，我们旨在研究 eRNA 触发炎症过程的机制，特别是与白细胞招募的不同步骤相关的机制。使用小鼠提睾肌微静脉的活体显微镜观察，eRNA（而非 DNA）在体内显着诱导白细胞粘附和迁移，其效果与肿瘤坏死因子-α (TNF-α) 的功能相当。在体外，eRNA 促进单核细胞在内皮细胞单层上和跨内皮细胞单层的粘附和迁移。 eRNA 诱导的体外单核细胞粘附是通过血管内皮生长因子 (VEGF)/VEGF 受体 2 系统的激活介导的，并通过针对细胞间粘附分子 1 或 β 2 整合素 Mac-1 的中和抗体而消除。此外，eRNA 以时间和浓度依赖性方式诱导单核细胞释放 TNF-α，这涉及 TNF-α 转换酶 (TACE) 以及核因子 kappa B 信号传导机制的激活。在体内，抑制 TACE 显着降低 eRNA 诱导的白细胞粘附。我们的研究结果证明，与组织/血管损伤有关的 eRNA 通过诱导白细胞募集和动员单核细胞中的促炎细胞因子来引发有效的炎症反应。
Extracellular RNA (eRNA), released from cells under conditions of injury or vascular disease, acts as potent prothrombotic factor and promotes vascular hyperpermeability related to oedema formation in vivo. In this study, we aimed to investigate the mechanism by which eRNA triggers inflammatory processes, particularly associated with different steps of leukocyte recruitment. Using intravital microscopy of murine cremaster muscle venules, eRNA (but not DNA) significantly induced leukocyte adhesion and transmigration in vivo, which was comparable in its effects to the function of tumour-necrosis-factor-alpha (TNF-alpha). In vitro, eRNA promoted adhesion and transmigration of monocytic cells on and across endothelial cell monolayers. eRNA-induced monocyte adhesion in vitro was mediated by activation of the vascular endothelial growth factor (VEGF)/VEGF-receptor-2 system and was abolished by neutralising antibodies against intercellular adhesion molecule-1 or the beta 2-integrin Mac-1. Additionally, eRNA induced the release of TNF-alpha from monocytic cells in a time- and concentration-dependent manner, which involved activation of TNF-alpha-converting enzyme (TACE) as well as the nuclear factor kappa B signalling machinery. In vivo, inhibiton of TACE significantly reduced eRNA-induced leukocyte adhesion. Our findings present evidence that eRNA in connection with tissue/vascular damage provokes a potent inflammatory response by inducing leukocyte recruitment and by mobilising proinflammatory cytokines from monocytes.