Interferon-γ inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress

Wensheng Lin, April Kemper, Jeffrey L. Dupree, Heather P. Harding, David Ron, Brian Popko

Research output: Contribution to journalArticlepeer-review

149 Scopus citations

Abstract

Interferon-γ (IFN-γ) is believed to play a deleterious role in the immune-mediated demyelinating disorder multiple sclerosis. Here we have exploited transgenic mice that ectopically express IFN-γ in a temporally controlled manner in the CNS to specifically study its effects on remyelination in the cuprizone-induced demyelination model and in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. CNS delivery of IFN-γ severely suppressed remyelination in both models and impaired the clinical recovery of the mice experiencing EAE. These observations correlated with a dramatic reduction of oligodendroglial repopulation in the demyelinated lesions. Moreover, we found that in cuprizone-treated mice the detrimental actions of IFN-γ were associated with endoplasmic reticulum (ER) stress in remyelinating oligodendrocytes. Compared with a wild-type genetic background, the presence of IFN-γ in mice heterozygous for a loss of function mutation in the pancreatic ER kinase (PERK), a kinase that responds specifically to ER stress, further reduced the percentage of remyelinated axons and oligodendrocyte numbers in cuprizone-induced demyelinated lesions. Thus, these data suggest that IFN-γ is capable of inhibiting remyelination in demyelinated lesions and that ER stress modulates the response of remyelinating oligodendrocytes to this cytokine.

Original languageEnglish (US)
Pages (from-to)1306-1318
Number of pages13
JournalBrain
Volume129
Issue number5
DOIs
StatePublished - May 2006

Bibliographical note

Funding Information:
This work was supported by grants to B.P. from the National Institutes of Health (NS34939), the National Multiple Sclerosis Society (RG 3291 A4/T) and the Myelin Repair Foundation and by NIH grants DK47119 and ES08681 to D.R. J.L.D. is the recipient of a Wadsworth Foundation Young Investigator Research Award. The authors acknowledge the helpful contribution of discussions with colleagues at the Myelin Repair Foundation. We are also indebted to Krystal Strand for critically reading the manuscript.

Keywords

  • ER stress
  • Interferon-γ
  • Oligodendrocyte
  • PERK
  • Remyelination

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