Deleterious role of IFNgamma in a toxic model of central nervous system demyelination.
Interferon-gamma (IFNgamma) is a pleiotropic cytokine that plays an important role in many inflammatory processes, including autoimmune diseases such as multiple sclerosis (MS). Demyelination is a hallmark of MS and a prominent pathological feature of several other inflammatory diseases of the central nervous system, including experimental autoimmune encephalomyelitis, an animal model of MS. Accordingly, in this study we followed the effect of IFNgamma in the demyelination and remyelination process by using an experimental autoimmune encephalomyelitis model of demyelination/remyelination after exposure of mice to the neurotoxic agent cuprizone. We show that demyelination in response to cuprizone is delayed in mice lacking the binding chain of IFNgamma receptor. In addition, IFNgammaR(-/-) mice exhibited an accelerated remyelination process after cuprizone was removed from the diet. Our results also indicate that the levels of IFNgamma were able to modulate the microglia/macrophage recruitment to the demyelinating areas. Moreover, the accelerated regenerative response showed by the IFNgammaR(-/-) mice was associated with a more efficient recruitment of oligodendrocyte precursor cells in the demyelinated areas. In conclusion, this study suggests that IFNgamma regulates the development and resolution of the demyelinating syndrome and may be associated with toxic effects on both mature oligodendrocytes and oligodendrocyte precursor cells.
Maña
Paula
P
Neurosciences Research Unit, The Canberra Hospital, Australian National University Medical School, The Canberra Hospital, PO Box 11, Woden, 2601, Canberra, Australia.
Liñares
David
D
Fordham
Sue
S
Staykova
Maria
M
Willenborg
David
D
D000818:Animals; D001921:Brain / Q000473:pathology; D002490:Central Nervous System / Q000473:pathology*; D003337:Corpus Callosum / Q000378:metabolism; D003471:Cuprizone; D016207:Cytokines / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced*; D004195:Disease Models, Animal; D005260:Female; D006133:Growth Substances / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D000096743:Interferon gamma Receptor
D003471:Cuprizone; D016207:Cytokines; D006133:Growth Substances; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor