Involvement of Interferon-γ in Microglial-Mediated Loss of Dopaminergic Neurons
| Autor: | Patrice D. Smith, Sylvie Faucher, Shawn Hayley, Ruth S. Slack, Hymie Anisman, Matthew P. Mount, Arman Lira, David S. Park, David Grimes |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Dopamine Cell Count Substantia nigra Interferon-gamma Mice chemistry.chemical_compound Dopaminergic Cell medicine Animals Humans Cells Cultured Aged Mice Knockout Neurons Cell Death Chemistry Pars compacta General Neuroscience MPTP Neurodegeneration Dopaminergic Parkinson Disease Articles Rotenone Middle Aged medicine.disease Coculture Techniques Cell biology Mice Inbred C57BL nervous system Microglia Neuroscience medicine.drug |
| Zdroj: | The Journal of Neuroscience. 27:3328-3337 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Growing evidence implicates microglia in the loss of dopaminergic neurons in Parkinson's disease (PD). However, factors mediating microglial activation in PD are poorly understood. Proinflammatory cytokines, such as interferon-γ (IFN-γ), orchestrate the actions of microglia. We report here that PD patients express significantly elevated levels of IFN-γ in their blood plasma. After this initial finding, we found thatIFN-γ-deficient mice displayed attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced substantia nigra pars compacta dopaminergic cell loss along with reduced loss of striatal tyrosine hydroxylase and dopamine transporter fiber density. MPTP-induced depletion of striatal dopamine and its metabolite DOPAC (3,4-dihydroxyphenylacetic acid), as well as ΔFosB, a marker of postsynaptic dysfunction, were also attenuated in these knock-out mice. Consistent with the role for IFN-γ in microglial activation, MPTP-induced morphological activation of microglia was abrogated compared with wild-type mice. To examine more mechanistically the role of IFN-γ in microglial activation, we evaluated the interactions between microglia and dopaminergic neurons in anin vitromixed microglia/midbrain neuron rotenone-induced death paradigm. In thisin vitroparadigm, dopaminergic neurons are selectively damaged by rotenone. Exogenous IFN-γ ligand alone and without rotenone resulted in dopaminergic cell loss, but only in the presence of microglia. The addition of an IFN-γ neutralizing antibody attenuated neuronal loss as a result of rotenone treatment. The presence of only wild-type microglia and not those deficient in IFN-γ receptor elicited significant dopaminergic cell loss when exposed to rotenone. Neurons deficient in IFN-γ receptor, however, did not display increased resistance to death. Finally, levels of IFN-γ message increased in microglia in response to rotenone. Together, these data suggest that IFN-γ participates in death of dopaminergic neurons by regulating microglial activity. |
| Databáze: | OpenAIRE |
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