Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury.
Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury.
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M1极化巨噬细胞外泌体miR-155通过激活NF-κB信号通路促进脊髓损伤后血管内皮细胞EndoMT并损害线粒体功能
DOI：
10.1016/j.redox.2021.101932
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发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Cai W
中科院分区：
文献类型：
--
作者：
Ge X;Tang P;Rong Y;Jiang D;Lu X;Ji C;Wang J;Huang C;Duan A;Liu Y;Chen X;Chen X;Xu Z;Wang F;Wang Z;Li X;Zhao W;Fan J;Liu W;Yin G;Cai W
病理学上，脊髓损伤（SCI）后血脊髓屏障（BSCB）的破坏导致大量外周巨噬细胞浸润到损伤区域并聚集在新生血管周围。在漏出的巨噬细胞中，M1极化的巨噬细胞占主导地位，并在整个SCI过程中起着至关重要的作用。本研究旨在探讨M1极化的骨髓源性巨噬细胞（M1-BMDMs）对血管内皮细胞的作用及其机制。微血管内皮细胞系bEnd.3细胞用条件培养基或来源于M1-BMDM的外泌体处理，然后评价内皮-间充质转化（EndoMT）和线粒体功能。给药后，我们发现来自M1-BMDMs的条件培养基或exosomes在体外和体内显著促进血管内皮细胞的EndoMT，从而加重SCI后BSCB的破坏。此外，线粒体功能障碍和活性氧（ROS）的积累也被检测到。此外，生物信息学分析表明，miR-155在M1极化的巨噬细胞和小胶质细胞中均上调。在实验中，miR-155的外泌体转移参与了M1-BMDM诱导的bEnd. 3细胞中EndoMT和线粒体ROS的产生，随后通过靶向下游细胞因子信号转导抑制因子6（SOCS 6）并抑制SOCS 6介导的p65泛素化和降解来激活NF-κB信号通路。最后，一系列的拯救实验进一步证实了外泌体miR 155/SOCS 6/p65轴调节血管内皮细胞的EndoMT过程和线粒体功能。总之，我们的工作揭示了描述SCI后巨噬细胞和血管内皮细胞之间通信的潜在机制，这可能有利于未来的研究，并有助于开发SCI的潜在治疗方法。SCI后BSCB被破坏，导致巨噬细胞浸润。来自M1极化巨噬细胞的外泌体促进血管内皮细胞中的EndoMT并损害线粒体功能。miR-155在源自M1极化巨噬细胞的外泌体中上调。外泌体miR-155/SOCS 6/p65轴参与血管内皮细胞的EndoMT和线粒体功能障碍
Pathologically, blood-spinal-cord-barrier (BSCB) disruption after spinal cord injury (SCI) leads to infiltration of numerous peripheral macrophages into injured areas and accumulation around newborn vessels. Among the leaked macrophages, M1-polarized macrophages are dominant and play a crucial role throughout the whole SCI process. The aim of our study was to investigate the effects of M1-polarized bone marrow-derived macrophages (M1-BMDMs) on vascular endothelial cells and their underlying mechanism. Microvascular endothelial cell line bEnd.3 cells were treated with conditioned medium or exosomes derived from M1-BMDMs, followed by evaluations of endothelial-to-mesenchymal transition (EndoMT) and mitochondrial function. After administration, we found conditioned medium or exosomes from M1-BMDMs significantly promoted EndoMT of vascular endothelial cells in vitro and in vivo, which aggravated BSCB disruption after SCI. In addition, significant dysfunction of mitochondria and accumulation of reactive oxygen species (ROS) were also detected. Furthermore, bioinformatics analysis demonstrated that miR-155 is upregulated in both M1-polarized macrophages and microglia. Experimentally, exosomal transfer of miR-155 participated in M1-BMDMs-induced EndoMT and mitochondrial ROS generation in bEnd.3 cells, and subsequently activated the NF-κB signaling pathway by targeting downstream suppressor of cytokine signaling 6 (SOCS6), and suppressing SOCS6-mediated p65 ubiquitination and degradation. Finally, a series of rescue assay further verified that exosomal miR155/SOCS6/p65 axis regulated the EndoMT process and mitochondrial function in vascular endothelial cells. In summary, our work revealed a potential mechanism describing the communications between macrophages and vascular endothelial cells after SCI which could benefit for future research and aid in the development of potential therapies for SCI. BSCB is disrupted after SCI leading to infiltration of macrophages. Exosomes from M1-polarized-macrophages promote EndoMT and impair mitochondrial function in vascular endothelial cells. miR-155 is upregulated in exosomes derived from M1-polarized macrophages. Exosomal miR-155/SOCS6/p65 axis is involved in EndoMT and mitochondrial dysfunction of vascular endothelial cells.
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影响因子：
8.8
作者：
Chen PY;Qin L;Barnes C;Charisse K;Yi T;Zhang X;Ali R;Medina PP;Yu J;Slack FJ;Anderson DG;Kotelianski V;Wang F;Tellides G;Simons M
通讯作者：
Simons M
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
25.7
作者：
Bala S;Csak T;Saha B;Zatsiorsky J;Kodys K;Catalano D;Satishchandran A;Szabo G
通讯作者：
Szabo G
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG
影响因子：
6.7
作者：
Jiang X;Andjelkovic AV;Zhu L;Yang T;Bennett MVL;Chen J;Keep RF;Shi Y
通讯作者：
Shi Y