Astrocyte-specific function of OTUB1 in experimental autoimmune encephalomyelitis

星形胶质细胞在实验性自身免疫性脑脊髓炎（EAE）中发挥重要的免疫调节作用，EAE是人类自身免疫性疾病多发性硬化的动物模型。以前，我们已经表明，星形胶质细胞特异性Fas配体通过诱导浸润性致脑炎T细胞凋亡有助于EAE的恢复。此外，我们发现A20，一种去泛素化酶（DUB），抑制星形胶质细胞中NF-κ B和STAT 1的活化，从而改善EAE。最近，另一种DUB，OTU去泛素化酶，泛素醛结合1（OTUB 1）已被证明是重要的调节NF-κ B和凋亡。然而，OTUB 1的体内功能在很大程度上是未知的。为了解决OTUB 1的星形胶质细胞特异性功能，我们产生了星形胶质细胞中选择性缺乏OTUB 1的小鼠。与对照小鼠相比，这些GFAP-Cre OTUB 1fl/fl小鼠发生了显著更严重的EAE，脊髓中T细胞、树突状细胞和巨噬细胞的浸润增加。与对照细胞相比，OTUB 1缺陷型星形胶质细胞在体外用IFN-γ刺激后产生显著更高水平的CXCL 10、CXCL 11和NOS 2。在此基础上，我们的目的是进一步阐明OTUB 1在EAE中的星形胶质细胞特异性调控机制和分子功能。

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.