Involvement of Interferon-γ in Microglial-Mediated Loss of Dopaminergic Neurons
Open Access
- 21 March 2007
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 27 (12), 3328-3337
- https://doi.org/10.1523/jneurosci.5321-06.2007
Abstract
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.Keywords
This publication has 61 references indexed in Scilit:
- Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOS pathwayApoptosis, 2006
- Activation of microglia by aggregated β-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-γ and IL-4 render them protectiveMolecular and Cellular Neuroscience, 2005
- Dopamine‐dependent neurotoxicity of lipopolysaccharide in substantia nigraThe FASEB Journal, 2004
- Inhibition of microglial activation by the herbal flavonoid baicalein attenuates inflammation-mediated degeneration of dopaminergic neuronsJournal of Neural Transmission, 2004
- Neurogenesis and stereological morphometry of calretinin‐immunoreactive GABAergic interneurons of the neostriatumJournal of Comparative Neurology, 2004
- Minocycline enhances MPTP toxicity to dopaminergic neuronsJournal of Neuroscience Research, 2003
- Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson's diseaseThe FASEB Journal, 2003
- Inflammatory processes in amyotrophic lateral sclerosisMuscle & Nerve, 2002
- Human T lymphotropic virus type I (HTLV-1) associated myelopathy acquired through a liver transplantJournal of Neurology, Neurosurgery & Psychiatry, 2001
- N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) suppresses microglial inducible nitric oxide synthase (iNOS) expression and activity induced by interferon-γ (IFN-γ)British Journal of Pharmacology, 2001