TY - JOUR
T1 - Interferon-γ Potentiates α-Synuclein-induced Neurotoxicity Linked to Toll-like Receptors 2 and 3 and Tumor Necrosis Factor-α in Murine Astrocytes
AU - Wang, Jintang
AU - Chen, Zheng
AU - Walston, Jeremy D.
AU - Gao, Peisong
AU - Gao, Maolong
AU - Leng, Sean X.
N1 - Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
KW - Astrocytes
KW - Cytokines
KW - Interferon-γ
KW - Neuroinflammation
KW - Toll-like receptors
KW - α-Synuclein
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U2 - 10.1007/s12035-019-1567-5
DO - 10.1007/s12035-019-1567-5
M3 - Article
C2 - 31098954
AN - SCOPUS:85066009721
SN - 0893-7648
VL - 56
SP - 7664
EP - 7679
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 11
ER -