ArticleMolecular neurobiology2019
Interferon-γ Potentiates α-Synuclein-induced Neurotoxicity Linked to Toll-like Receptors 2 and 3 and Tumor Necrosis Factor-α in Murine Astrocytes.
Article in Molecular neurobiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 22 citations in OpenAlex.
- Beneficial perspective onFrontiers in immunology · 2025Review
- Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drivesFrontiers in cellular neuroscience · 2025Review
- Molecular Mechanisms Linking Omega-3 Fatty Acids and the Gut-Brain Axis.Molecules (Basel, Switzerland) · 2024Review
- Relationship among α‑synuclein, aging and inflammation in Parkinson's disease (Review).Experimental and therapeutic medicine · 2024Review
- Identification of TLR2 as a Key Target in Neuroinflammation in Vascular Dementia.Frontiers in genetics · 2022Article
- The Specific Role of Reactive Astrocytes in Stroke.Frontiers in cellular neuroscience · 2022Review
- Toll-Like Receptor 2 Attenuates Traumatic Brain Injury-Induced Neural Stem Cell Proliferation in Dentate Gyrus of Rats.Neural plasticity · 2020Article
- The Potential Role of SARS-COV-2 in the Pathogenesis of Parkinson's Disease.Frontiers in neurology · 2020Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
α-Synuclein (α-syn), a metabolite of neurons, induces glial activation and neuroinflammation and participates in pathogenesis of neurodegenerative diseases. This inflammatory response involves activation of toll-like receptors (TLRs) and its neurotoxic outcomes such as cytokine expression and release. However, regulatory role of cytokines on α-syn-induced neurotoxicity is still unclear. In this study, we used interferon (IFN)-γ to costimulate primary astrocytes with wild-type or A53T mutant α-syn, and evaluated inflammatory pathway activation. Four α-syn concentrations (0.5, 2, 8 and 20 μg/mL, 24 h) and four α-syn time-points (3, 12, 24 and 48 h, 2 μg/mL) were chosen to coincubate with one IFN-γ concentration (2 ng/mL). IFN-γ alone upregulated expressions of TLR3 and tumor necrosis factor (TNF)-α (mRNA level), and A53T mutant or wild-type α-syn alone activated the pathway components including TLR2, TLR3, nuclear factor-κB, TNF-α and interleukin (IL)-1β. Additive application of IFN-γ amplified this activation effect except for IL-1β at mRNA and protein levels or TNF-α release, displaying a synergistic effect of α-syn and IFN-γ. Blocking TLR2 other than TLR4 suppressed TLR3, TLR2 and TNF-α expressions induced by α-syn or plus IFN-γ, reflecting an interaction of TLR2 and TLR3 in TNF-α expression. These data collectively showed that IFN-γ potentiated α-syn stimulation and inflammatory outcomes via TLR2, TLR3 and TNF-α other than IL-1β in astrocytes, suggesting that involvement of IFN-γ in α-syn-induced innate immunity may be required for initiation and maintenance of glial activation, a novel neurotoxic mechanism underlying pathogenesis of neurodegenerative diseases. Graphical Abstract IFN-γ potentiates α-synuclein (A53T or wild-type)-induced innate immunity, involving expressions of TLR2, TLR3, NF-κB, and TNF-α, other than IL-1β. This effect is suppressed by blockage of TLR2 other than TLR4, reflecting an interaction of TLR2 and TLR3 in TNF-α expression. Thus, involvement of IFN-γ in α-syn-induced neurotoxicity may be required for initiation and maintenance of glial activation, a novel neurotoxic mechanism underlying pathogenesis of neurodegenerative diseases.
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