Detrimental and Beneficial Effects of Interferon-gamma on Oligodendrocytes and the Myelination/Remyelination Process

Strand, Krystle D.

Detrimental and Beneficial Effects of Interferon-gamma on Oligodendrocytes and the Myelination/Remyelination Process Public Deposited

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March 20, 2019

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Strand, Krystle D.
- Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum

Abstract

Interferon-gamma (IFN-γ) is a pro-inflammatory cytokine that is believed to play a key role in the pathogenesis of immune-mediated demyelinating disorders of the central nervous system by exerting direct deleterious effects on oligodendrocytes, the myelinating cells of the CNS. Increasing evidence predicts that the effect of IFN-γ on oligodendrocytes in culture and in vivo will depend on the developmental stage of the cells and the timing of IFN-γ expression relative to myelination/remyelination. We hypothesize that selected genes will be expressed by developmentally different oligodendrocytes when exposed to IFN-γ. In order to elucidate the molecular mechanisms driving these effects, we used microarrays to quantitatively compare the transcriptional response of 1) cultured developing and mature primary oligodendrocytes exposed to IFN-γ, and 2) the corpus collosum exposed to IFN-γ in vivo during, and two weeks following, a cuprizone-induced demyelinating insult, measured at the point of peak demyelination and at the crest of remyelination. There was a significant change in the expression of numerous genes in both the in vitro and in vivo systems as a result of IFN-γ exposure. Most dramatic were changes in the expression of genes involved in antigen presentation and protein processing, the immune response, the endoplasmic reticulum stress response, apoptosis, and the oxidative stress response. Moreover, immature oligodendrocytes appeared more responsive and vulnerable than mature oligodendrocytes to IFN-γ exposure in vitro, and the timing of IFN-γ induction influenced the transcriptional response in vivo. Early IFN-γ exposure demonstrated evidence of a deleterious effect, while later IFN-γ suggested a protective effect, particularly during remyelination.

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