Astrocyte-specific function of OTUB1 in experimental autoimmune encephalomyelitis

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.

DFG Programme Research Grants