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TNFα promotes proliferation of oligodendrocyte progenitors and remyelination

Nature Neuroscience volume 4, pages 1116–1122 (2001)Cite this article

Abstract

Here we used mice lacking tumor necrosis factor-α (TNFα) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone. Unexpectedly, the lack of TNFα led to a significant delay in remyelination as assessed by histology, immunohistochemistry for myelin proteins and electron microscopy coupled with morphometric analysis. Failure of repair correlated with a reduction in the pool of proliferating oligodendrocyte progenitors (bromodeoxyuridine-labeled NG2+ cells) followed by a reduction in the number of mature oligodendrocytes. Analysis of mice lacking TNF receptor 1 (TNFR1) or TNFR2 indicated that TNFR2, not TNFR1, is critical to oligodendrocyte regeneration. This unexpected reparative role for TNFα in the CNS is important for understanding oligodendrocyte regeneration/proliferation, nerve remyelination and the design of new therapeutics for demyelinating diseases.

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Figure 1: TNFα and receptor expression during demyelination and remyelination.
Figure 2: Effects of TNFα during demyelination.
Figure 3: Effects of TNFα, TNFR1 and TNFR2 during remyelination.
Figure 4: Analysis of oligodendrocyte progenitors during remyelination.
Figure 5: The lack of lymphocyte involvement in remyelination.

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Acknowledgements

This work was supported by NIH grants NS34190 (J.P.-Y.T.) and NS24453 (K.S.), as well as NMSS grants RG185 (J.P.-Y.T.) and RG254B (G.K.M.). We thank L. Old for the use of the TNFα−/− mice and R. Bagnell for his expertise in electron microscopy.

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Author notes

  1. Jeff Mason

    Present address: Department of Pathology, Columbia University, 630 West 168th street, New York, New York, 10032, USA

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, School of Medicine CB7295, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Heather A. Arnett & Jenny P.-Y. Ting

  2. Curriculum in Neurobiology, CB7250, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Heather A. Arnett, Jeff Mason, Kinuko Suzuki, Glenn K. Matsushima & Jenny P.-Y. Ting

  3. Ludwig Institute, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, 10017, New York, USA

    Mike Marino

  4. Department of Pathology and Laboratory Medicine, CB7525, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Kinuko Suzuki

  5. Department of Microbiology and Immunology, CB7290, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Glenn K. Matsushima & Jenny P.-Y. Ting

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Correspondence to Jenny P.-Y. Ting.

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Arnett, H., Mason, J., Marino, M. et al. TNFα promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4, 1116–1122 (2001). https://doi.org/10.1038/nn738

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