TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination.
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.
Arnett
H A
HA
Lineberger Comprehensive Cancer Center, School of Medicine CB7295, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Mason
J
J
Marino
M
M
Suzuki
K
K
Matsushima
G K
GK
Ting
J P
JP
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D001923:Brain Chemistry; D003337:Corpus Callosum / Q000378:metabolism / Q000648:ultrastructure; D003471:Cuprizone / Q000008:administration & dosage / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013234:Stem Cells / Q000502:physiology* / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; D008996:Monoamine Oxidase Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D003471:Cuprizone