α-Synuclein activates innate immunity but suppresses interferon-γ expression in murine astrocytes

Jintang Wang, Zheng Chen, Jeremy D. Walston, Peisong Gao, Maolong Gao, Sean X. Leng

Research output: Contribution to journalArticlepeer-review

Abstract

Glial activation and neuroinflammation contribute to pathogenesis of neurodegenerative diseases, linked to neuron loss and dysfunction. α-Synuclein (α-syn), as a metabolite of neuron, can induce microglia activation to trigger innate immune response. However, whether α-syn, as well as its mutants (A53T, A30P, and E46K), induces astrocyte activation and inflammatory response is not fully elucidated. In this study, we used A53T mutant and wild-type α-syns to stimulate primary astrocytes in dose- and time-dependent manners (0.5, 2, 8, and 20 μg/ml for 24 hr or 3, 12, 24, and 48 hr at 2 μg/ml), and evaluated activation of several canonical inflammatory pathway components. The results showed that A53T mutant or wild-type α-syn significantly upregulated mRNA expression of toll-like receptor (TLR)2, TLR3, nuclear factor-κB and interleukin (IL)-1β, displaying a pattern of positive dose–effect correlation or negative time–effect correlation. Such upregulation was confirmed at protein levels of TLR2 (at 20 μg/ml), TLR3 (at most doses), and IL-1β (at 3 hr) by western blotting. Blockage of TLR2 other than TLR4 inhibited TLR3 and IL-1β mRNA expressions. By contrast, interferon (IFN)-γ was significantly downregulated at mRNA, protein, and protein release levels, especially at high concentrations of α-syns or early time-points. These findings indicate that α-syn was a TLRs-mediated immunogenic agent (A53T mutant stronger than wild-type α-syn). The stimulation patterns suggest that persistent release and accumulation of α-syn is required for the maintenance of innate immunity activation, and IFN-γ expression inhibition by α-syn suggests a novel immune molecule interaction mechanism underlying pathogenesis of neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)1583-1599
Number of pages17
JournalEuropean Journal of Neuroscience
Volume48
Issue number1
DOIs
StatePublished - Jul 2018

Keywords

  • astrocytes
  • cytokines
  • innate immunity
  • interferon-γ
  • toll-like receptors
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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