Pharmacological inhibition of STING reduces neuroinflammation-mediated damage post-traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of interferon genes (STING) and its downstream type-I interferon (IFN) signalling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating the detrimental neuroinflammatory response after TBI. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. EXPERIMENTAL APPROACH: This study investigated the neuroprotective effects of the small-molecule STING inhibitor n-(4-iodophenyl)-5-nitrofuran-2-carboxamide (C-176) in the controlled cortical impact mouse model of TBI in 10- to 12-week-old male mice. Thirty minutes post-controlled cortical impact surgery, a single 750-nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2 h and 24 h post-TBI. KEY RESULTS: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24 h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines Tnf-α, Il-1ß and Cxcl10 compared to their vehicle-treated counterparts 2 h post-TBI. CONCLUSION AND IMPLICATIONS: This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma-induced inflammation and neuroprotective potential.

Biomaterial Strategies for Restorative Therapies in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurological disorder, in which dopaminergic midbrain neurons degenerate, leading to dopamine depletion that is associated with neuronal death. In this Review, we initially describe the pathogenesis of PD and established therapies that unfortunately only delay progression of the disease. With a rapidly escalating incidence in PD, there is an urgent need to develop new therapies that not only halt progression but even reverse degeneration. Biomaterials are playing critical roles in these new therapies which include controlled and site-specific delivery of neurotrophins, increased engraftment of implanted neural stem cells, and redirection of endogenous stem cell populations away from their niche to encourage reparative mechanisms. This Review will therefore cover important design features of biomaterials used in regenerative medicine and tissue engineering strategies targeted at PD.

The Complexity of the cGAS-STING Pathway in CNS Pathologies.

Neuroinflammation driven by type-I interferons in the CNS is well established to exacerbate the progression of many CNS pathologies both acute and chronic. The role of adaptor protein Stimulator of Interferon Genes (STING) is increasingly appreciated to instigate type-I IFN-mediated neuroinflammation. As an upstream regulator of type-I IFNs, STING modulation presents a novel therapeutic opportunity to mediate inflammation in the CNS. This review will detail the current knowledge of protective and detrimental STING activity in acute and chronic CNS pathologies and the current therapeutic avenues being explored.

STING-Mediated Autophagy Is Protective against H2O2-Induced Cell Death.

Stimulator of interferon genes (STING)-mediated type-I interferon signaling is a well characterized instigator of the innate immune response following bacterial or viral infections in the periphery. Emerging evidence has recently linked STING to various neuropathological conditions, however, both protective and deleterious effects of the pathway have been reported. Elevated oxidative stress, such as neuroinflammation, is a feature of a number of neuropathologies, therefore, this study investigated the role of the STING pathway in cell death induced by elevated oxidative stress. Here, we report that the H2O2-induced activation of the STING pathway is protective against cell death in wildtype (WT) MEFSV40 cells as compared to STING-/- MEF SV40 cells. This protective effect of STING can be attributed, in part, to an increase in autophagy flux with an increased LC3II/I ratio identified in H2O2-treated WT cells as compared to STING-/- cells. STING-/- cells also exhibited impaired autophagic flux as indicated by p62, LC3-II and LAMP2 accumulation following H2O2 treatment, suggestive of an impairment at the autophagosome-lysosomal fusion step. This indicates a previously unrecognized role for STING in maintaining efficient autophagy flux and protecting against H2O2-induced cell death. This finding supports a multifaceted role for the STING pathway in the underlying cellular mechanisms contributing to the pathogenesis of neurological disorders.

An altered glial phenotype in the NL3R451C mouse model of autism.

Autism Spectrum Disorder (ASD; autism) is a neurodevelopmental disorder characterised by deficits in social communication, and restricted and/or repetitive behaviours. While the precise pathophysiologies are unclear, increasing evidence supports a role for dysregulated neuroinflammation in the brain with potential effects on synapse function. Here, we studied characteristics of microglia and astrocytes in the Neuroligin-3 (NL3R451C) mouse model of autism since these cell types are involved in regulating both immune and synapse function. We observed increased microglial density in the dentate gyrus (DG) of NL3R451C mice without morphological differences. In contrast, WT and NL3R451C mice had similar astrocyte density but astrocyte branch length, the number of branch points, as well as cell radius and area were reduced in the DG of NL3R451C mice. Because retraction of astrocytic processes has been linked to altered synaptic transmission and dendrite formation, we assessed for regional changes in pre- and postsynaptic protein expression in the cortex, striatum and cerebellum in NL3R451C mice. NL3R451C mice showed increased striatal postsynaptic density 95 (PSD-95) protein levels and decreased cortical expression of synaptosomal-associated protein 25 (SNAP-25). These changes could contribute to dysregulated neurotransmission and cognition deficits previously reported in these mice.

Abrogation of type-I interferon signalling alters the microglial response to Aß1-42.

Neuroinflammation and accompanying microglial dysfunction are now appreciated to be involved in Alzheimer's disease (AD) pathogenesis. Critical to the process of neuroinflammation are the type-I interferon (IFN) family of cytokines. Efforts to phenotypically characterize microglia within AD identify distinct populations associated with type-I IFN signalling, yet how this affects underlying microglial function is yet to be fully elucidated. Here we demonstrate that Aß1-42 exposure increases bioactive levels of type-I IFN produced by primary microglia alongside increased expression of type-I IFN related genes. Primary microglia isolated from brains of APPswePS1ΔE9 mice with ablated type-I IFN signalling show an increased phagocytic ability to uptake FITC-Aß1-42. Correlative assessment of plaque sizes in aged APPswePS1ΔE9 mice with abrogated type-I IFN signalling show unchanged deposition levels. Microglia from these mice did however show alterations in morphology. This data further highlights the role of type-I IFN signalling within microglia and identifies a role in phagocytosis. As such, targeting both microglial and global type-I IFN signalling presents as a novel therapeutic strategy for AD management.

Genetic Modulators of Traumatic Brain Injury in Animal Models and the Impact of Sex-Dependent Effects.

Traumatic brain injury (TBI) is a major health problem causing disability and death worldwide. There is no effective treatment, due in part to the complexity of the injury pathology and factors affecting its outcome. The extent of brain injury depends on the type of insult, age, sex, lifestyle, genetic risk factors, socioeconomic status, other co-injuries, and underlying health problems. This review discusses the genes that have been directly tested in TBI models, and whether their effects are known to be sex-dependent. Sex differences can affect the incidence, symptom onset, pathology, and clinical outcomes following injury. Adult males are more susceptible at the acute phase and females show greater injury in the chronic phase. TBI is not restricted to a single sex; despite variations in the degree of symptom onset and severity, it is important to consider both female and male animals in TBI pre-clinical research studies.

The use of bioactive matrices in regenerative therapies for traumatic brain injury.

Functional deficits due to neuronal loss are a common theme across multiple neuropathologies, including traumatic brain injury (TBI). Apart from mitigating cell death, another approach to treating brain injuries involves re-establishing the neural circuitry at the lesion site by utilizing exogeneous and/or endogenous stem cells to achieve functional recovery. While there has been limited success, the emergence of new bioactive matrices that promote neural repair introduces new perspectives on the development of regenerative therapies for TBI. This review briefly discusses current development on cell-based therapies and the use of bioactive matrices, hydrogels in particular, when incorporated in regenerative therapies. Desirable characteristics of bioactive matrices that have been shown to augment neural repair in TBI models were identified and further discussed. Understanding the relative outcomes of newly developed biomaterials implanted in vivo can better guide the development of biomaterials as a therapeutic strategy, for biomaterial-based cellular therapies are still in their nascent stages. Nonetheless, the value of bioactive matrices as a treatment for acute brain injuries should be appreciated and further developed. STATEMENT OF SIGNIFICANCE: Cell-based therapies have received attention as an alternative therapeutic strategy to improve clinical outcome post-traumatic brain injury but have achieved limited success. Whilst the incorporation of newly developed biomaterials in regenerative therapies has shown promise in augmenting neural repair, studies have revealed new hurdles which must be overcome to improve their therapeutic efficacy. This review discusses the recent development of cell-based therapies with a specific focus on the use of bioactive matrices in the form of hydrogels, to complement cell transplantation within the injured brain. Moreover, this review consolidates in vivo animal studies that demonstrate relative functional outcome upon the implantation of different biomaterials to highlight their desirable traits to guide their development for regenerative therapies in traumatic brain injury.

Migration and Differentiation of Neural Stem Cells Diverted From the Subventricular Zone by an Injectable Self-Assembling ß-Peptide Hydrogel.

Neural stem cells, which are confined in localised niches are unable to repair large brain lesions because of an inability to migrate long distances and engraft. To overcome these problems, previous research has demonstrated the use of biomaterial implants to redirect increased numbers of endogenous neural stem cell populations. However, the fate of the diverted neural stem cells and their progeny remains unknown. Here we show that neural stem cells originating from the subventricular zone can migrate to the cortex with the aid of a long-lasting injectable hydrogel within a mouse brain. Specifically, large numbers of neuroblasts were diverted to the cortex through a self-assembling ß-peptide hydrogel that acted as a tract from the subventricular zone to the cortex of transgenic mice (NestinCreERT2:R26eYFP) in which neuroblasts and their progeny are permanently fluorescently labelled. Moreover, neuroblasts differentiated into neurons and astrocytes 35 days post implantation, and the neuroblast-derived neurons were Syn1 positive suggesting integration into existing neural circuitry. In addition, astrocytes co-localised with neuroblasts along the hydrogel tract, suggesting that they assisted migration and simulated pathways similar to the native rostral migratory stream. Lower levels of astrocytes were found at the boundary of hydrogels with encapsulated brain-derived neurotrophic factor, comparing with hydrogel implants alone.

Targeting high-mobility group box protein 1 (HMGB1) in pediatric traumatic brain injury: Chronic neuroinflammatory, behavioral, and epileptogenic consequences.

High mobility group box protein-1 (HMGB1) has been implicated as a key mediator of neuroinflammation and neurodegeneration in a range of neurological conditions including traumatic brain injury (TBI) and epilepsy. To date, however, most studies have examined only acute outcomes, and the adult brain. We have recently demonstrated HMGB1 release after experimental TBI in the pediatric mouse. This study therefore examined the chronic consequences of acute HMGB1 inhibition in the same model, to test the hypothesis that HMGB1 is a pivotal mediator of neuropathological, neurobehavioral, and epilepsy outcomes in pediatric TBI. HMGB1 was inhibited by treatment with 50 mg/kg i.p. Glycyrrhizin (Gly), compared to vehicle controls, commencing 1 h prior to moderate TBI or sham surgery in post-natal day 21 mice. We first demonstrated that Gly reduced brain HMGB1 levels and brain edema at an acute time point of 3 days post-injury. Subsequent analysis over a chronic time course found that pediatric TBI resulted in short-term spatial memory and motor learning deficits alongside an apparent increase in hippocampal microglial reactivity, which was prevented in Gly-treated TBI mice. In contrast, Gly treatment did not reduce the severity of evoked seizures, the proportion of animals exhibiting chronic spontaneous seizure activity, or cortical tissue loss. Together, our findings contribute to a growing appreciation for HMGB1's role in neuropathology and associated behavioral outcomes after TBI. However, further work is needed to fully elucidate the contribution of HMGB1 to epileptogenesis in this context.

The influence of neuroinflammation in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social communication and restricted or repetitive behaviours. The clinical presentation of ASD is highly variable and diagnosis is based on the presence of impaired social communication and repetitive and/or restricted behaviours. Although the precise pathophysiologies underlying ASD are unclear, growing evidence supports a role for dysregulated neuroinflammation. The potential involvement of microglia and astrocytes reactive to inflammatory stimuli in ASD has generated much interest due to their varied roles including in mounting an immune response and regulating synaptic function. Increased numbers of reactive microglial and astrocytes in both ASD postmortem tissue and animal models have been reported. Whether dysregulation of glial subtypes exacerbates alterations in neural connectivity in the brain of autistic patients is not well explored. A role for the gut-brain axis involving microbial-immune-neuronal cross talk is also a growing area of neuroinflammation research. Greater understanding of these interactions under patho/physiological conditions and the identification of consistent immune profile abnormalities can potentially lead to more reliable diagnostic measures and treatments in ASD.

The involvement of microglia in Alzheimer's disease: a new dog in the fight.

First described clinically in 1906, Alzheimer's disease (AD) is the most common neurodegenerative disease and form of dementia worldwide. Despite its prevalence, only five therapies are currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. A multitude of experimental evidence has suggested that the once thought inconsequential process of neuroinflammation does, in fact, contribute to the AD pathogenesis. One such CNS cell type critical to this process are microglia. Plastic in nature with varied roles, microglia are emerging as key contributors to AD pathology. This review will focus on the role of microglia in the neuroinflammatory response in AD, highlighting recent studies implicating aberrant changes in microglial function in disease progression. Of critical note is that with these advances, a reconceptualization of the framework in which we view microglia is required. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Age-dependent release of high-mobility group box protein-1 and cellular neuroinflammation after traumatic brain injury in mice.

Accumulating research suggests that children may be more vulnerable to poor long-term outcomes after traumatic brain injury (TBI) compared to adults. The neuroinflammatory response, known to contribute to neuropathology after TBI, appears to differ depending upon age-at-insult, although this response has not been well-characterized. Elevated levels of a key initiator of inflammation, high-mobility group box protein 1 (HMGB1), have been associated with worsened outcomes after TBI in young patients. This study therefore aimed to characterize the acute time course of key mediators of the inflammatory cascade, including HMGB1, after pediatric and adult TBI. Male C57Bl/6 mice were subjected to severe controlled cortical impact or a sham control surgery, at either early adulthood (8-10 weeks) or a pediatric age (3 weeks). Cortical tissue was collected for Western blot detection of astrocyte and microglial activation (GFAP and CD68) and HMGB1 at 2 hr, 6 hr, 24 hr, 3 days, and 7 days postinjury, and serum was collected for enzyme-linked immunoassays to quantify peripheral HMGB1. An additional cohort of brains was harvested at 3 day postinjury for immunofluorescence staining. Results demonstrated a temporal profile of CD68, GFAP, and HMGB1 after TBI relative to sham, which differed between the adult and pediatric cohorts. An increase in peripheral HMGB1 was found in serum from pediatric TBI mice, which was not evident in adult serum. Together, these findings demonstrate that HMGB1 and the downstream cellular inflammatory response are influenced by age-at-insult, which may be an important consideration for treatment strategies aiming to ameliorate this response after TBI.

High-throughput screening for small molecule inhibitors of the type-I interferon signaling pathway.

Interferons (IFNs) are cytokines with fundamental roles in resistance to infections, cancer and other diseases. Type-I IFNs, interferon α (IFN-α) and interferon ß (IFN-ß), act through a shared receptor complex (IFNAR) comprised of IFNAR1 and IFNAR2 subunits. Binding of type-I IFN to IFNAR1 will robustly activate Janus activated kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Aberrant activation of the type-I IFN response results in a spectrum of disorders called interferonopathies. The purpose of this research is to develop an assay for high-throughput screening (HTS) of small molecule inhibitors of the type-I IFN signaling pathway. Inhibition of type-I IFN signaling can be beneficial in terms of therapeutic use and understanding the underlying mechanism of action. We report here a HTS campaign with the secreted embryonic alkaline phosphatase (SEAP) reporter gene assay against 32,000 compounds which yielded 25 confirmed hits. These compounds were subsequently characterized for their cytotoxicity, effects on STAT phosphorylation and activities in IFN regulatory factor (IRF) transcription.

STING-mediated type-I interferons contribute to the neuroinflammatory process and detrimental effects following traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) represents a major cause of disability and death worldwide with sustained neuroinflammation and autophagy dysfunction contributing to the cellular damage. Stimulator of interferon genes (STING)-induced type-I interferon (IFN) signalling is known to be essential in mounting the innate immune response against infections and cell injury in the periphery, but its role in the CNS remains unclear. We previously identified the type-I IFN pathway as a key mediator of neuroinflammation and neuronal cell death in TBI. However, the modulation of the type-I IFN and neuroinflammatory responses by STING and its contribution to autophagy and neuronal cell death after TBI has not been explored. METHODS: C57BL/6J wild-type (WT) and STING-/- mice (8-10-week-old males) were subjected to controlled cortical impact (CCI) surgery and brains analysed by QPCR, Western blot and immunohistochemical analyses at 2 h or 24 h. STING expression was also analysed by QPCR in post-mortem human brain samples. RESULTS: A significant upregulation in STING expression was identified in late trauma human brain samples that was confirmed in wild-type mice at 2 h and 24 h after CCI. This correlated with an elevated pro-inflammatory cytokine profile with increased TNF-α, IL-6, IL-1ß and type-I IFN (IFN-α and IFN-ß) levels. This expression was suppressed in the STING-/- mice with a smaller lesion volume in the knockout animals at 24 h post CCI. Wild-type mice also displayed increased levels of autophagy markers, LC3-II, p62 and LAMP2 after TBI; however, STING-/- mice showed reduced LAMP2 expression suggesting a role for STING in driving dysfunctional autophagy after TBI. CONCLUSION: Our data implicates a detrimental role for STING in mediating the TBI-induced neuroinflammatory response and autophagy dysfunction, potentially identifying a new therapeutic target for reducing cellular damage in TBI.

Type-I interferon pathway in neuroinflammation and neurodegeneration: focus on Alzheimer's disease.

Past research in Alzheimer's disease (AD) has largely been driven by the amyloid hypothesis; the accompanying neuroinflammation seen in AD has been assumed to be consequential and not disease modifying or causative. However, recent data from both clinical and preclinical studies have established that the immune-driven neuroinflammation contributes to AD pathology. Key evidence for the involvement of neuroinflammation in AD includes enhanced microglial and astroglial activation in the brains of AD patients, increased pro-inflammatory cytokine burden in AD brains, and epidemiological evidence that chronic non-steroidal anti-inflammatory drug use prior to disease onset leads to a lower incidence of AD. Identifying critical mediators controlling this neuroinflammation will prove beneficial in developing anti-inflammatory therapies for the treatment of AD. The type-I interferons (IFNs) are pleiotropic cytokines that control pro-inflammatory cytokine secretion and are master regulators of the innate immune response that impact on disorders of the central nervous system. This review provides evidence that the type-I IFNs play a critical role in the exacerbation of neuroinflammation and actively contribute to the progression of AD.

Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke.

Neuroinflammation contributes significantly to the pathophysiology of stroke. Here we test the hypothesis that the type I interferon receptor (IFNAR1) plays a critical role in neural injury after stroke by regulating the resultant pro-inflammatory environment. Wild-type and IFNAR1-/- primary murine neurons and glia were exposed to oxygen glucose deprivation (OGD) and cell viability was assessed. Transient cerebral ischemia/reperfusion injury was induced by mid-cerebral artery occlusion (MCAO) in wild-type and IFNAR1-/- and IFNAR2-/- mice in vivo, and infarct size, and molecular parameters measured. To block IFNAR1 signalling, wild-type mice were treated with a blocking monoclonal antibody directed to IFNAR1 (MAR-1) and MCAO was performed. Quantitative PCR confirmed MCAO in wild-type mice induced a robust type-I interferon gene regulatory signature. Primary cultured IFNAR1-deficient neurons were found to be protected from cell death when exposed to OGD in contrast to primary cultured IFNAR1-deficient glial cells. IFNAR1-/- mice demonstrated a decreased infarct size (24.9 ± 7.1 mm3 n = 8) compared to wild-type controls (65.1 ± 4.8 mm3 n = 8). Western blot and immunohistochemistry showed alterations in Akt and Stat-3 phosphorylation profiles in the IFNAR1-/- brain. MAR-1 injection into WT mice (i.v. 0.5 mg 60 min prior to MCAO) resulted in a 60% decrease in infarct size when compared to the IgG control. IFNAR2-/- mice failed to display the neuroprotective phenotype seen in IFNAR1-/- mice after MCAO. Our data proposes that central nervous system signalling through IFNAR1 is a previously unrecognised factor that is critical to neural injury after stroke.

Type-I interferons mediate the neuroinflammatory response and neurotoxicity induced by rotenone.

Evidence from post-mortem human brains, animal studies and cell culture models has implicated neuroinflammation in the aetiology of chronic neuropathologies including Alzheimer's and Parkinson's diseases. Although the neuroinflammatory response is considered detrimental in contributing to these pathologies, the underlying mechanisms are still not well understood. The type-I interferons (IFNs) have been well characterised in the periphery and are known to initiate/modulate the immune response. Recently, they have been implicated in ageing and we have also demonstrated increased type-I IFN expression in post-mortem human Alzheimer's and Parkinson's disease brains. We hypothesise that the type-I IFNs are key drivers of the damaging, self-perpetuating pro-inflammatory response that contributes to these chronic neuropathologies. In support of this, we have recently confirmed in models of Alzheimer's and Parkinson's disease that mice lacking the type-I IFN receptor (IFNAR1), display an attenuated neuroinflammatory response with subsequent neuroprotection. To further investigate type-I IFN-mediated neuroinflammation and the specific CNS cell types involved, this study treated primary cultured wild-type and IFNAR1-/- neurons or mixed glia with the mitochondrial complex I inhibitor, rotenone. Wild-type neurons and glia treated with 3 nM and 25 nM rotenone, respectively, exhibited a pro-inflammatory response, including increased type-I IFN expression that was attenuated in cells lacking IFNAR1. Reduced type-I IFN signalling in IFNAR1-/- neurons also conferred protection against caspase-3-mediated rotenone-induced cell death. Further, this reduced pro-inflammatory response in the IFNAR1-/- glia subsequently diminished their neurotoxic effects to wild-type neurons. In support of this, we confirmed that therapeutically targeting the type-I IFN glial response to rotenone through a specific IFNAR1 blocking monoclonal antibody was neuroprotective. Our data has confirmed that both neurons and glia contribute to the pro-inflammatory response induced by rotenone with attenuation of this response beneficial in reducing neuronal cell death. Read the Editorial Comment for this article on page 9.

Oxidation of Iron under Physiologically Relevant Conditions in Biological Fluids from Healthy and Alzheimer's Disease Subjects.

Ferroxidase activity has been reported to be altered in various biological fluids in neurodegenerative disease, but the sources contributing to the altered activity are uncertain. Here we assay fractions of serum and cerebrospinal fluid with a newly validated triplex ferroxidase assay. Our data indicate that while ceruloplasmin, a multicopper ferroxidase, is the predominant source of serum activity, activity in CSF predominantly derives from a <10 kDa component, specifically from polyanions such as citrate and phosphate. We confirm that in human biological samples, ceruloplasmin activity in serum is decreased in Alzheimer's disease, but in CSF a reduction of activity in Alzheimer's disease originates from the polyanion component.

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

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.