Abstract
Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) 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 TNF alpha 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 TNF alpha in the CNS is important for understanding oligodendrocyte regeneration/proliferation, nerve remyelination and the design of new therapeutics for demyelinating diseases.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Apoptosis
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B-Lymphocytes / metabolism
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Brain Chemistry
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Corpus Callosum / metabolism
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Corpus Callosum / ultrastructure
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Cuprizone / administration & dosage
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Cuprizone / toxicity
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Demyelinating Diseases / chemically induced
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Disease Models, Animal
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Humans
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Immunohistochemistry
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In Situ Nick-End Labeling
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Macrophages / metabolism
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Male
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Mice
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Mice, Knockout
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Microglia / metabolism
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Monoamine Oxidase Inhibitors / pharmacology
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Myelin Sheath / metabolism*
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Myelin Sheath / pathology
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Myelin Sheath / ultrastructure
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Oligodendroglia / cytology
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Oligodendroglia / drug effects
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Oligodendroglia / physiology*
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Stem Cells / physiology*
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Stem Cells / ultrastructure
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
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Up-Regulation
Substances
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Antigens, CD
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Monoamine Oxidase Inhibitors
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Tumor Necrosis Factor-alpha
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Cuprizone