IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-gamma and TNF-alpha in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN-gamma and TNF-alpha remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-gamma R signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-gamma and TNF-alpha KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-gamma and TNF-alpha is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-gamma signaling, together with the contribution of TNF-alpha, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism. Cell Death and Disease (2011) 2, e142; doi: 10.1038/cddis.2011.17; published online 7 April 2011