Journal Article

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 and Brian Popko

in Brain

Published on behalf of The Guarantors of Brain

Volume 129, issue 5, pages 1306-1318
Published in print May 2006 | ISSN: 0006-8950
Published online February 2006 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awl044
Interferon-γ inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress

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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.

Keywords: ER stress; interferon-γ; oligodendrocyte; PERK; remyelination; BIP = binding immunoglobulin protein; CHOP = CAATT enhancer-binding protein homologous protein; DAPI = 4′,6-diamidino-2-phenylindole; EAE = experimental autoimmune encephalomyelitis; ELISA = enzyme-linked immunosorbent assay; EM = electron microscope; ER = endoplasmic reticulum; GFAP = glial fibrillary acidic protein; IFN-γ = interferon-γ; IL = interleukin; iNOs = inducible nitric oxide synthase; MBP = myelin basic protein; MHC-I = major histocompatibility complex class I; OPCs = oligodendrocyte precursors; PBS = phosphate-buffered saline; PERK = pancreatic ER kinase; p-eIF-2α = phosphorylated eukaryotic translation initiation factor-2α; PID = post-immunization day; TNF-α = tumour necrosis factor-α; tTA = tetracycline-controlled transactivator

Journal Article.  8405 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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