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

Zhixin Lei, Yuan Yue, Sarrabeth Stone, Shuangchan Wu, Wensheng Lin

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4 Scopus citations

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 κB (NF-κB). NF-κB plays a critical role in MS and EAE; however, the effects of NF-κB activation on oligodendrocytes in these diseases remain elusive. Herein, we generated a mouse model that allow for activation of NF-κB specifically in oligodendrocytes and found that enhanced NF-κB 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-κB 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-κB activation in oligodendrocytes, and were completely rescued by enhanced NF-κB activation in oligodendrocytes (female mice). These findings suggest that NF-κB activation accounts for the cytoprotective effects of PERK activation on oligodendrocytes in MS and EAE. SIGNIFICANCE STATEMENT Nuclear factor κB (NF-κB) is activated in oligodendrocytes in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE); however, the role of NF-κB activation in oligodendrocytes in MS and EAE remains elusive. Herein, we generated a mouse model that allows for activation of NF-κB selectively in oligodendrocytes and demonstrated that NF-κB activation prevented oligodendrocyte death and myelin damage in the EAE model. We further demonstrated that NF-κB activation contributed to the protective effects of pancreatic ER kinase (PERK) activation on oligodendrocytes in the EAE model. As such, this work will facilitate the development of new treatments that enhance oligodendrocyte survival in MS patients by targeting the PERK-NF-κB pathway.

Original languageEnglish (US)
Pages (from-to)6444-6456
Number of pages13
JournalJournal of Neuroscience
Volume40
Issue number33
DOIs
StatePublished - Aug 12 2020

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health Grants NS094151 and NS105689 (to W.L.). We thank Dr. Klaus-Armin Nave (Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany) for providing the CNP/Cre mice. We also thank Dr. Juan E. Abrahante Lloréns (University of Minnesota Informatics Institute) for conducting bioinformatics analysis of RNA-sequencing data.

Funding Information:
Received May 12, 2020; revised June 22, 2020; accepted June 30, 2020. Author contributions: Z.L. and W.L. designed research; Z.L., Y.Y., S.S., and S.W. performed research; Z.L., Y.Y., and W.L. analyzed data; Z.L. and W.L. wrote the paper. The authors declare no competing financial interests. This study was supported by National Institutes of Health Grants NS094151 and NS105689 (to W.L.). We thank Dr. Klaus-Armin Nave (Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany) for providing the CNP/Cre mice. We also thank Dr. Juan E. Abrahante Lloréns (University of Minnesota Informatics Institute) for conducting bioinformatics analysis of RNA-sequencing data. Correspondence should be addressed to Wensheng Lin at linw@umn.edu. https://doi.org/10.1523/JNEUROSCI.1156-20.2020 Copyright © 2020 the authors

Publisher Copyright:
© 2020 the authors

Keywords

  • A20
  • Demyelination
  • EAE
  • NF-jB
  • Oligodendrocyte
  • PERK
  • Inflammation Mediators/metabolism
  • Mice, Inbred C57BL
  • Male
  • Mice, Transgenic
  • Animals
  • eIF-2 Kinase/metabolism
  • Multiple Sclerosis/metabolism
  • Oligodendroglia/metabolism
  • Female
  • NF-kappa B/metabolism
  • Encephalomyelitis, Autoimmune, Experimental/metabolism

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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