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Astrocyte-specific function of OTUB1 in experimental autoimmune encephalomyelitis

OTUB1在实验性自身免疫性脑脊髓炎中的星形胶质细胞特异性功能

基本信息

批准号：
302097871
负责人：
Dr. Xu Wang, Ph.D.
金额：
--
依托单位：
Institut für Medizinische Mikrobiologie und Krankenhaushygiene
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/302097871?language=en
关键词：
Astrocyte specific function OTUB1 experimental

项目摘要

Astrocytes play an important immunoregulatory role in experimental autoimmune encephalomyelitis (EAE), an animal model for the human autoimmune disease multiple sclerosis. Previously, we have shown that astrocyte-specific Fas ligand contributes to EAE recovery by inducing apoptosis of infiltrating encephalitogenic T cells. Additionally, we identified that A20, a deubiquitinase (DUB), inhibits NF-kB and STAT1 activation in astrocytes, which ameliorates EAE. Recently, another DUB, OTU deubiquitinase, ubiquitin aldehyde binding 1 (OTUB1) has been shown to be important for the regulation of NF-kB and apoptosis. However, the in vivo function of OTUB1 is largely unknown. To address the astrocyte-specific function of OTUB1, we generated mice lacking OTUB1 selectively in astrocytes. These GFAP-Cre OTUB1fl/fl mice developed a significantly more severe EAE with increased infiltration of T cells, dendritic cells and macrophages in the spinal cord as compared to control mice. Compared to control cells, OTUB1-deficient astrocytes produced significantly higher levels of CXCL10, CXCL11, and NOS2 upon stimulation with IFN-gamma in vitro. Based on these results, we aim to further elucidate the astrocyte-specific regulatory mechanisms and molecular function of OTUB1 in EAE in the applied project.

星形胶质细胞在实验性自身免疫性脑脊髓炎(EAE)中发挥着重要的免疫调节作用，EAE是人类多发性硬化症的动物模型。此前，我们已经证明星形胶质细胞特异性的Fas配体通过诱导浸润性生脑T细胞的凋亡来促进EAE的恢复。此外，我们发现A20，一种脱泛素酶(DUB)，可以抑制星形胶质细胞中的NF-kB和STAT1的激活，从而改善EAE。最近，另一种DUB，OTU脱泛素酶，泛素醛结合1(OTUB1)被证明在核因子-kB的调节和细胞凋亡中起重要作用。然而，OTUB1的体内功能在很大程度上是未知的。为了解决OTUB1的星形胶质细胞特异性功能，我们产生了选择性地在星形胶质细胞中缺失OTUB1的小鼠。与对照组相比，这些GFAP-CRE OTUB1fl/fl小鼠发生了明显更严重的EAE，脊髓中T细胞、树突状细胞和巨噬细胞的渗透增加。与对照细胞相比，体外培养的OTUB1缺陷星形胶质细胞在干扰素-γ刺激下产生明显更高水平的CXCL10、CXCL11和NOS2。基于这些结果，我们的目标是在应用项目中进一步阐明OTUB1在EAE中的星形胶质细胞特异性调控机制和分子功能。