Type-1 interferons contribute to the neuroinflammatory response and disease progression of the MPTP mouse model of Parkinson's disease

• Published in: Glia 2016-09, Vol.64 (9), p.1590-1604
• Main Authors: Main, Bevan S., Zhang, Moses, Brody, Kate M., Ayton, Scott, Frugier, Tony, Steer, David, Finkelstein, David, Crack, Peter J., Taylor, Juliet M.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Death - genetics; Cytokines - metabolism; Disease Models, Animal; Dopamine - metabolism; Dopaminergic Neurons - metabolism; Inflammation - genetics; Interferon; Interferon Type I - genetics; Interferon Type I - metabolism; interferons; Mice, Inbred C57BL; Mice, Knockout; microglia; Microglia - metabolism; MPTP; neuroinflammation; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson's disease; Rodents; Substantia Nigra - pathology
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23028

Type‐1 interferons (IFNs) are pleiotropic cytokines with a critical role in the initiation and regulation of the pro‐inflammatory response. However, the contribution of the type‐1 IFNs to CNS disorders, specifically chronic neuropathologies such as Parkinson's disease is still unknown. Here, we report increased type‐1 IFN signaling in both post mortem human Parkinson's disease samples and in the 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) mouse model. In response to MPTP, mice lacking the type‐1 IFN receptor (IFNAR1−/−) displayed decreased type‐1 IFN signaling, an attenuated pro‐inflammatory response and reduced loss of dopaminergic neurons. The neuroprotective potential of targeting the type‐1 IFN pathway was confirmed by reduced neuroinflammation and DA cell death in mice treated with a blocking monoclonal IFNAR1 (MAR‐1) antibody. The MPTP/MAR‐1 treated mice also displayed increased striatal dopamine levels and improved behavioural outcomes compared to their MPTP/IgG controls. These data, implicate for the first time, a deleterious role for the type‐1 IFNs as key modulators of the early neuroinflammatory response and therefore the neuronal cell death in Parkinson's disease. GLIA 2016;64:1590–1604 Main Points Type‐1 IFNs are upregulated in human post‐mortem Parkinson's disease brains and in the MPTP mouse model. Genetically or therapeutically targeting type‐1 IFN signaling attenuates neuroinflammation and dopaminergic cell death induced by MPTP.