NF-jB activation accounts for the cytoprotective effects of PERK activation on oligodendrocytes during EAE

Previous studies demonstrate that activation of pancreatic ER kinase (PERK) protects oligodendrocytes against inflammation in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Interestingly, data indicate that the cytoprotective effects of PERK activation on oligodendrocytes during EAE are not mediated by activating transcription factor 4 (ATF4) but are accompanied by activation of nuclear factor jB (NF-jB). NF-jB plays a critical role in MS and EAE; however, the effects of NF-jB activation on oligodendrocytes in these diseases remain elusive. Herein, we generated a mouse model that allow for activation of NF-jB specifically in oligodendrocytes and found that enhanced NF-jB activation in oligodendrocytes had a minimal effect on their viability and function under normal conditions (both male and female mice). Interestingly, we found that enhanced NF-jB activation in oligodendrocytes attenuated EAE disease severity and ameliorated EAE-induced oligodendrocyte loss, demyelination, and axon degeneration, without affecting inflammation (female mice). Moreover, we showed that the detrimental effects of PERK inactivation in oligodendrocytes in EAE were accompanied by impaired NF-jB activation in oligodendrocytes, and were completely rescued by enhanced NF-jB activation in oligodendrocytes (female mice). These findings suggest that NF-jB activation accounts for the cytoprotective effects of PERK activation on oligodendrocytes in MS and EAE.