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

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.

Chronic neurodegeneration induces type I interferon synthesis via STING, shaping microglial phenotype and accelerating disease progression

“…Conversely, Tnfa showed similar disease‐associated IFNAR1‐dependent induction in both APP/PS1 and ME7 models (Figure and (Minter et al, ). Both Il1b and Tnfa are reported to be elevated in the MPTP model of Parkinson's disease, and IFNAR1 deficiency was also shown to reverse these, although fold‐increases in these transcripts were relatively small and rather variable (Main et al, ).…”

“…The principal cells responsible for IFN‐I production during systemic viral infection include macrophages and plasmacytoid dendritic cells, but it is clear that most cell types in the central nervous system (CNS) can mount IFN‐I responses (Blank et al, ; Owens, Khorooshi, Wlodarczyk, & Asgari, ). These responses may arise in response to systemic viral infection, circulating IFNα, or viral mimetics such as poly inosinic: poly cytidylic acid (Murray et al, ; Wang, Campbell, & Zhang, ) or in response to brain injury and neurodegeneration (Field, Campion, Warren, Murray, & Cunningham, ; Hosmane et al, ; Khorooshi & Owens, ; Main et al, ; Minter et al, ; Wang, Yang, & Zhang, ). Recently, both astrocytes and microglia have been shown to express a number of DNA sensors and to respond to DNA stimulation with robust IFN‐I responses (Cox et al, ).…”

“…All type I IFNs can signal via the heterodimeric interferon α/β receptor (IFNAR), which classically signals via a JAK/STAT pathway leading to the upregulation of IFN‐stimulated genes (ISGs) (Schoggins & Rice, ), and generation of IFNAR1‐deficient mice (Hwang et al, ) has facilitated attempts to understand the role of IFN‐I in neurodegenerative disease. With respect to chronic neurodegenerative processes, IFNAR1 deficiency resulted in modestly slowed disease progression in SOD1(G93A) model of amyotrophic lateral sclerosis (Wang et al, ) and reduced dopaminergic cell death in the MPTP model of Parkinson's disease (Main et al, ). Conversely, loss of dopaminergic neurons was observed in IFNβ −/− mice (Ejlerskov et al, ).…”

Reduced cortical excitatory synapse number in APOE4 mice is associated with increased calcineurin activity

“…RNA was extracted from cortex brain tissue using TRIzol® reagent (Invitrogen) and RT-QPCR was performed as described previously 23 using the Prism 7900HT fast sequence detection system (Applied Biosystems). Taqman probes were used to analyse GAPDH (Mm99999915_m1), Ppp3ca (Mm01317678_m1) and Ppp3cb (Mm00920265_m1) under the following cycle conditions, 50°C for 2 minutes, 95°C for 20seconds, (95°C for 1 second, 60°C for 20 seconds)× 40 repeats.…”

Microbial Immuno-Communication in Neurodegenerative Diseases

“…Importantly, aged mice supplemented with a type-1 IFN neutralizing antibody displayed reduced CCL11 expression, attenuated hippocampal glial reactivity, elevated BDNF production, and improved neurogenesis (Baruch et al, 2014). A dysregulated type-1 IFN signature has been observed in aging disorders, that appear to be regulated by the microbiome, including AD (Taylor et al, 2014; Minter et al, 2016a) and PD (Main et al, 2016) and it is now considered that a balance of type-1 and type-2 IFN signaling at the CP is required to impart healthy brain immunity and aging (Deczkowska et al, 2016). …”