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

Glia. 2016 Sep;64(9):1590-604. doi: 10.1002/glia.23028. Epub 2016 Jul 12.

Abstract

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.

Keywords: MPTP; Parkinson's disease; interferons; microglia; neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism*
  • Inflammation / genetics
  • Interferon Type I / genetics*
  • Interferon Type I / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Substantia Nigra / pathology

Substances

  • Cytokines
  • Interferon Type I
  • Dopamine