NF-κB Activation Accounts for the Cytoprotective Effects of PERK Activation on Oligodendrocytes during EAE

Abstract

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.

Microglial Nox2 Plays a Key Role in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…Since ROS activates NF-κB signaling, which modulates gene expression in diverse cellular processes such as innate immune response ( 29 , 30 ), we next determined if NF-κB plays were required for the expression of inflammatory transcription factors in our EAE model. To do this, we co-stained the active form of NF-κB (pNF-κB) with NeuN or CD11b ( Figure 6G ).…”

Adsorption of Gaseous Elemental Mercury by Ferric‐Chloride‐Modified Activated Carbon Under Low‐Temperature Conditions

“…The Hg 0 removal efficiency decreases with the increase of the relative humidity. It is mainly due to the water molecules attached to the surface of AC leading part of the micropores clogged, which reduced the surface area of Hg 0 adsorption and hindered the contact of Hg 0 with the active sites . As a result, both the physisorption and chemisorption were weakened.…”

RelB and Neuroinflammation

“…It has been shown that p65 aids in survival of oligodendrocytes in vitro [ 131 , 132 , 133 ]. However, constitutively active IKKβ in oligodendrocytes of mice had little effect on the survival and functions of oligodendrocytes under normal conditions [ 134 ]. By contrast, during EAE, these mice had reduced demyelination, oligodendrocyte death, and axon degeneration, resulting in overall decreased disease severity [ 134 ].…”

“…However, constitutively active IKKβ in oligodendrocytes of mice had little effect on the survival and functions of oligodendrocytes under normal conditions [ 134 ]. By contrast, during EAE, these mice had reduced demyelination, oligodendrocyte death, and axon degeneration, resulting in overall decreased disease severity [ 134 ]. This phenotype was attributed to the activation of p65 and increased p65-dependent oligodendrocyte survival [ 133 , 134 ].…”

“…By contrast, during EAE, these mice had reduced demyelination, oligodendrocyte death, and axon degeneration, resulting in overall decreased disease severity [ 134 ]. This phenotype was attributed to the activation of p65 and increased p65-dependent oligodendrocyte survival [ 133 , 134 ]. Interestingly, in a mouse expressing a IκBαΔN super-repressor (lacking N terminus and thus resistant to proteasomal degradation) in oligodendrocytes, there was no effect on demyelination or remyelination in a cuprizone model of MS [ 133 ].…”