IFN-c signaling, with the synergistic contribution of TNF-a, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease

Abstract

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we

investigate the function of IFN-c and TNF-a in experimental models of Parkinson’s disease and analyze their relation with local

glial cell activation. It was found that IFN-c and TNF-a 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-cR signaling

in both microglial and astroglial cells. In addition, experiments performed in IFN-c and TNF-a KO mice treated with MPTP

revealed that, even before dopaminergic cell death can be observed, the presence of IFN-c and TNF-a 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-c signaling, together with the

contribution of TNF-a, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism.