JAK/STAT signaling pathway-mediated microRNA-181b promoted blood-brain barrier impairment by targeting sphingosine-1-phosphate receptor 1 in septic rats.
JAK/STAT signaling pathway-mediated microRNA-181b promoted blood-brain barrier impairment by targeting sphingosine-1-phosphate receptor 1 in septic rats.
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JAK/STAT信号通路介导的microRNA-181b通过靶向1-磷酸鞘氨醇受体1促进脓毒症大鼠血脑屏障损伤
DOI：
10.21037/atm-20-7024
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发表时间：
2020-11
影响因子：
--
通讯作者：
Wen MY
中科院分区：
文献类型：
--
作者：
Chen SL;Cai GX;Ding HG;Liu XQ;Wang ZH;Jing YW;Han YL;Jiang WQ;Wen MY
背景血脑屏障（BBB）受损在脓毒症相关脑病（SAE）的发病机制中起重要作用。然而，分子机制知之甚少。本研究旨在探讨Janus激酶/信号转导和转录激活因子（JAK/STAT）信号通路、microRNA（miR）-181b及其靶基因在脓毒症中的调控关系。方法建立假手术、脓毒症、脓毒症+STAT 3抑制剂（Stattic）和脓毒症+miR-181 b抑制剂[脓毒症+ anta-miR-181 b] 4种大鼠模型。对于体外实验，将大鼠脑微血管内皮细胞（rBMEC）和大鼠脑星形胶质细胞（rAstrocytes）与从假手术、脓毒症和脓毒症+ anta-miR-181 b大鼠收获的10%血清一起培养。染色质免疫沉淀-定量聚合酶链反应（ChIP-QPCR）分析检测JAK/STAT 3信号核心转录复合物在miR-181 b启动子区的结合和富集。采用双荧光素酶报告基因检测miR-181 b及其靶基因。测定rBMEC的细胞粘附率。结果脓毒症组miR-181 b、p-JAK 2、p-STAT 3和C/EBPβ的表达水平较假手术组明显升高。STAT 3抑制剂通过下调miR-181 b的表达阻止BBB损伤。此外，miR-181 b靶向鞘氨醇-1-磷酸受体1（S1 PR 1）和神经钙蛋白δ（NCALD）。上调miR-181 b表达可显著降低rBMEC的细胞粘附率。miR-181 b抑制剂的施用通过增加S1 PR 1和NCALD的表达来减少对BBB的损伤，这再次证明miR-181 b负调节SIPR 1和NCALD以诱导BBB损伤。结论JAK 2/STAT 3信号通路诱导miR-181 b表达，通过下调S1 PR 1表达，降低血脑屏障细胞粘附，促进血脑屏障损伤。这些发现有力地表明JAK 2/STAT 3/miR-181 b轴是保护败血症诱导的BBB损伤的治疗靶点。
Background Blood-brain barrier (BBB) impairment plays a significant role in the pathogenesis of sepsis-associated encephalopathy (SAE). However, the molecular mechanisms are poorly understood. In the present study, we aimed to investigate the regulatory relationship between the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, microRNA (miR)-181b and its target genes in sepsis in vivo and in vitro. Methods Four rat models (sham, sepsis, sepsis plus STAT3 inhibitor (Stattic), and sepsis plus miR-181b inhibitor [sepsis + anta-miR-181b]) were established. For the in vitro experiments, rat brain microvascular endothelial cells (rBMECs) and rat brain astrocytes (rAstrocytes) were cultured with 10% serum harvested from sham, sepsis, and sepsis + anta-miR-181b rats. Chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-QPCR) analysis was carried out to detect the binding and enrichment of the JAK/STAT3 signal core transcription complex in the miR-181b promoter region. Dual-luciferase reporter gene assay was conducted to test miR-181b and its target genes. The cell adhesion rate of rBMECs was also measured. Results During our investigations, the expression levels of miR-181b, p-JAK2, p-STAT3, and C/EBPβ were found to be significantly increased in the septic rats compared with the sham rats. STAT3 inhibitor halted BBB damage by downregulating the expression of miR-181b. In addition, miR-181b targeted sphingosine-1-phosphate receptor 1 (S1PR1) and neurocalcin delta (NCALD). The up-regulated miR-181b significantly decreased the cell adhesion rate of rBMECs. The administration of miR-181b inhibitor reduced damage to the BBB through increasing the expression of S1PR1 and NCALD, which again proved that miR-181b negatively regulates SIPR1 and NCALD to induce BBB damage. Conclusions Our study demonstrated that JAK2/STAT3 signaling pathway induced expression of miR-181b, which promoted BBB impairment in rats with sepsis by downregulating S1PR1 and decreasing BBB cell adhesion. These findings strongly suggest JAK2/STAT3/miR-181b axis as therapeutic target in protecting against sepsis-induced BBB damage.
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影响因子：
11.1
作者：
Dan C;Jinjun B;Zi-Chun H;Lin M;Wei C;Xu Z;Ri Z;Shun C;Wen-Zhu S;Qing-Cai J;Wu Y
通讯作者：
Wu Y
鉴定一组五种血清 miRNA 作为帕金森病的生物标志物。
影响因子：
4.1
作者：
Ding, Haixia;Huang, Zhen;Zhang, Junfeng
通讯作者：
Zhang, Junfeng
DOI：
10.4049/jimmunol.1302280
发表时间：
2014-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bosmann M;Russkamp NF;Strobl B;Roewe J;Balouzian L;Pache F;Radsak MP;van Rooijen N;Zetoune FS;Sarma JV;Núñez G;Müller M;Murray PJ;Ward PA
通讯作者：
Ward PA
影响因子：
4
作者：
Guo, Rui;Fan, Gang;Lu, Zhiming
通讯作者：
Lu, Zhiming
影响因子：
3.1
作者：
Feng, Anlin;Rice, Amanda D.;Wang, Ting
通讯作者：
Wang, Ting