Endothelial ETS1 inhibition exacerbate blood-brain barrier dysfunction in multiple sclerosis through inducing endothelial-to-mesenchymal transition.
Endothelial ETS1 inhibition exacerbate blood-brain barrier dysfunction in multiple sclerosis through inducing endothelial-to-mesenchymal transition.
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内皮 ETS1 抑制通过诱导内皮间质转化加剧多发性硬化症中的血脑屏障功能障碍
DOI：
10.1038/s41419-022-04888-5
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发表时间：
2022-05-14
影响因子：
9
通讯作者：
Hu, Bo
中科院分区：
文献类型：
--
作者：
Luo, Yan;Yang, Hang;Wan, Yan;Yang, Sibo;Wu, Jiehong;Chen, Shengcai;Li, Yanan;Jin, Huijuan;He, Quanwei;Zhu, Dong-Ya;Zhou, Yifan;Hu, Bo
血脑屏障（BBB）功能障碍已被认为是多发性硬化的早期病理特征和促成因素。内皮-间质转化是一个与内皮功能障碍相关的过程，导致血管稳定性和屏障功能的破坏，但其在多发性硬化症中的功能后果仍不清楚。在这里，我们证明了内皮细胞向间充质细胞的转化伴随着血脑屏障功能障碍的几种神经系统疾病，特别是在多发性硬化症。在MS及其动物模型实验性自身免疫性脑脊髓炎中，内皮细胞（EC）中高度表达并对炎症状态做出反应的转录因子ETS 1的活性在中枢神经系统（CNS）EC中受到抑制。我们确定ETS 1作为内皮-间充质转化（EndMT）的中心调节因子，与屏障完整性的损害有关。这些表型和功能改变可进一步诱导多发性硬化的高通透性、免疫浸润和器官纤维化，从而促进疾病进展。总之，这些结果证明了EndMT在血脑屏障功能障碍中的功能作用，并提出ETS 1作为EndMT的潜在转录开关，以靶向多发性硬化症的发展。
Blood–brain barrier (BBB) dysfunction has been recognized as an early pathological feature and contributing factor in multiple sclerosis. Endothelial-to-mesenchymal transition is a process associated with endothelial dysfunction leading to the disruption of vessel stability and barrier function, yet its functional consequence in multiple sclerosis remains unclear. Here, we demonstrated that endothelial-to-mesenchymal transition accompanied the blood–brain barrier dysfunction in several neurological disorders, especially in multiple sclerosis. The activity of transcription factor ETS1, which is highly expressed in endothelial cells (ECs) and responded to an inflammatory condition, is suppressed in the central nervous system (CNS) ECs in MS and its animal model experimental autoimmune encephalomyelitis. We identify ETS1 as a central regulator of endothelial-to-mesenchymal transition (EndMT) associated with the compromise of barrier integrity. These phenotypical and functional alterations can further induce high permeability, immune infiltration, and organ fibrosis in multiple sclerosis, thus promoting disease progression. Together, these results demonstrate a functional role of EndMT in blood–brain barrier dysfunction and propose ETS1 as a potential transcriptional switch of EndMT to target the development of multiple sclerosis.
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DOI：
10.1093/brain/awv203
发表时间：
2015-09
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Cramer SP;Modvig S;Simonsen HJ;Frederiksen JL;Larsson HB
通讯作者：
Larsson HB
影响因子：
30.5
作者：
Du, Changsheng;Liu, Chang;Pei, Gang
通讯作者：
Pei, Gang
影响因子：
16.6
作者：
Larochelle C;Uphaus T;Broux B;Gowing E;Paterka M;Michel L;Dudvarski Stankovic N;Bicker F;Lemaître F;Prat A;Schmidt MHH;Zipp F
通讯作者：
Zipp F
影响因子：
8.7
作者：
Goverman JM
通讯作者：
Goverman JM
影响因子：
5.3
作者：
Bhowmick, Saurav;D'Mello, Veera;Abdul-Muneer, P. M.
通讯作者：
Abdul-Muneer, P. M.