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Microglia Signaling Pathway Reporters Unveiled Manganese Activation of the Interferon/STAT1 Pathway and Its

Valeri V Mossine1,2, James K Waters3, Grace Y Sun4

  • 1Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA. mossinev@missouri.edu.

Molecular Neurobiology
|May 4, 2023
PubMed

Insights

Manganese (Mn) triggers specific interferon pathways in microglia, contributing to Parkinson-like symptoms. Dietary polyphenols, particularly certain flavonoids, can mitigate these effects, suggesting a potential therapeutic avenue for manganism.

Area of Science:

  • Neuroscience
  • Toxicology
  • Immunology

Background:

  • Neuroinflammation in the central nervous system (CNS) is linked to manganese (Mn)-induced Parkinson-like syndromes.
  • The precise molecular mechanisms underlying manganism remain incompletely understood.

Purpose of the Study:

  • To investigate the effects of manganese (II) on specific transcriptional activities in microglia.
  • To explore the potential of flavonoids in mitigating manganese-induced neuroinflammation and cytotoxicity.

Main Methods:

  • Utilized an in vitro neuroinflammation model with murine BV-2 microglia stably transfected with signaling pathway reporter constructs.
  • Assessed transcriptional activity of NF-κB, AP-1, STAT1, STAT3, Nrf2, and MTF-1 using luciferase assays.
  • Evaluated cellular viability and the impact of 64 natural and synthetic flavonoids on manganese (II) effects.

Main Results:

  • Manganese (II) specifically activated type I and type II interferon-induced signaling pathways in microglia.
  • Weak activation of NF-κB was observed with Mn(II) and Ba(II) treatment.
  • Certain flavonoids demonstrated cytoprotective effects, while others enhanced Mn(II) cytotoxicity; many attenuated Mn(II)-induced GAS activity.

Conclusions:

  • Manganese (II) is identified as a specific inducer of interferon-dependent pathways in microglia.
  • Dietary polyphenols, specifically flavonoids, show potential in mitigating manganese-induced neuroinflammation and cytotoxicity.
  • The protective mechanisms of flavonoids against manganese in microglia may not rely solely on metal chelation or antioxidant activity.
Keywords:
ApigeninEGCGInterferon-sensitive response element ISREManganeseMyricetinpiggyBac transposon

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