Introduction: Neuroinflammation has recently been proposed as contributing to the dopaminergic (DA) cell death observed in Parkinson’s disease (PD). Key players in the neuroinflammatory cascade are the type-I interferons (IFNs), however the role these cytokines play in PD has not been explored. We propose that type-I IFNs contribute to the progression and exacerbation of neuronal cell death in PD.
Methods and Results: This study confirmed a 3-fold up-regulation in the type-I IFN, IFNα in human post mortem PD brains (Australian Brain Bank, n=10, p<0.05). In addition, brains from wildtype mice exposed to MPTP (4x10mg/kg) display elevated levels of IFNβ (QPCR analysis) at day-3 post-MPTP compared to sham control mice brains. Increased immunohistochemical expression of phosphorylated Stat-3, a downstream mediator of type-I IFN signalling, was also identified in DA neurons of the substantia nigra. Significantly, other pro-inflammatory cytokines, IL-1β and TNFα were not upregulated until day-7 (n=6, p<0.001). Activation of type-I IFN signalling was also identified in BE(2)M17 neuroblastoma cells and primary neurons in response to the neurotoxin, rotenone (500nM and 25nM) as confirmed by increased Stat-3 phosphorylation (western blot analysis) and elevated IFNα and IFNβ expression (QPCR analysis). A protective effect of reduced type-I IFN signalling in response to rotenone (500nM) was identified with IFNα receptor-1 (IFNAR1) knockdown M17 cells displaying increased cell viability by MTT assay compared to cells expressing a negative control shRNA construct (83.73±4.20% versus 66.19±2.91% (n=5, p<0.05)). This protection against rotenone-induced cell death correlated with reduced mRNA expression of type-I IFNs and IL1-β.
Conclusion: These results have implicated the type-I IFNs in mediating the pro-inflammatory response in both animal and cellular models of PD and in human patients. The type-I IFN pathway may be a novel target in reducing neuroinflammation and thus limiting the neuronal cell damage in PD.