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Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2020-03-09 , DOI: 10.1172/jci130308
Zhilin Li , Emilia A. Korhonen , Arianna Merlini , Judith Strauss , Eleonoora Wihuri , Harri Nurmi , Salli Antila , Jennifer Paech , Urban Deutsch , Britta Engelhardt , Sudhakar Chintharlapalli , Gou Young Koh , Alexander Flügel , Kari Alitalo

Angiopoietin-2 (Ang2), a ligand of the endothelial Tie2 tyrosine kinase, is involved in vascular inflammation and leakage in critically ill patients. However, the role of Ang2 in demyelinating central nervous system (CNS) autoimmune diseases is unknown. Here, we report that Ang2 is critically involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis. Ang2 expression was induced in CNS autoimmunity, and transgenic mice overexpressing Ang2 specifically in endothelial cells (ECs) developed a significantly more severe EAE. In contrast, treatment with Ang2-blocking Abs ameliorated neuroinflammation and decreased spinal cord demyelination and leukocyte infiltration into the CNS. Similarly, Ang2-binding and Tie2-activating Ab attenuated the development of CNS autoimmune disease. Ang2 blockade inhibited expression of EC adhesion molecules, improved blood-brain barrier integrity, and decreased expression of genes involved in antigen presentation and proinflammatory responses of microglia and macrophages, which was accompanied by inhibition of α5β1 integrin activation in microglia. Taken together, our data suggest that Ang2 provides a target for increasing Tie2 activation in ECs and inhibiting proinflammatory polarization of CNS myeloid cells via α5β1 integrin in neuroinflammation. Thus, Ang2 targeting may serve as a therapeutic option for the treatment of CNS autoimmune disease.

中文翻译:

血管生成素2阻滞剂通过抑制白细胞募集进入中枢神经系统来改善自身免疫性神经炎症

血管生成素2(Ang2)是内皮Tie2酪氨酸激酶的配体,与危重患者的血管炎症和渗漏有关。但是,Ang2在脱髓鞘中枢神经系统(CNS)自身免疫性疾病中的作用尚不清楚。在这里,我们报告Ang2关键参与实验性自身免疫性脑脊髓炎(EAE),多发性硬化的啮齿动物模型的发病机理。在CNS自身免疫中诱导了Ang2的表达,而在内皮细胞(ECs)中特异表达Ang2的转基因小鼠发展出了更为严重的EAE。相反,用Ang2阻断Abs治疗可减轻神经炎症,并减少脊髓脱髓鞘和白细胞向CNS的浸润。同样,Ang2结合和Tie2激活抗体减弱了中枢神经系统自身免疫性疾病的发展。5 β 1整联在小胶质细胞活化。总之,我们的数据表明,Ang2的提供了一个目标在EC中增加Tie2活化,抑制CNS的促炎偏振髓经由α细胞5 β 1整联在神经炎症。因此,Ang2靶向可作为治疗CNS自身免疫疾病的治疗选择。
更新日期:2020-04-03
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