Manganese-induced reactive oxygen species activate IκB kinase to upregulate YY1 and impair glutamate transporter EAAT2 function in human astrocytes in vitro

Asha Rizor, Edward Pajarillo, Ivan Nyarko-Danquah, Alexis Digman, Leyah Mooneyham, Deok Soo Son, Michael Aschner, Eunsook Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Dysregulation of the astrocytic glutamate transporter excitatory amino acid transporter 2 (EAAT2) is associated with several neurological disorders, including Parkinson's disease, Alzheimer's disease, and manganism, the latter induced by chronic exposure to high levels of manganese (Mn). Mechanisms of Mn-induced neurotoxicity include impairment of EAAT2 function secondary to the activation of the transcription factor Yin Yang 1 (YY1) by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). However, the upstream mechanisms by which Mn-induced NF-κB activates YY1 remain to be elucidated. In the present study, we used the H4 human astrocyte cell line to test if Mn activates YY1 through the canonical NF-κB signaling pathway, leading to EAAT2 repression. The results demonstrate that Mn exposure induced phosphorylation of the upstream kinase IκB kinase (IKK-β), leading to NF-κB p65 translocation, increased YY1 promoter activity, mRNA/protein levels, and consequently repressed EAAT2. Results also demonstrated that Mn-induced oxidative stress and subsequent TNF-α production were upstream of IKK-β activation, as antioxidants attenuated Mn-induced TNF-α production and IKK-β activation. Moreover, TNF-α inhibition attenuated the Mn-induced activation of IKK-β and YY1. Taken together, Mn-induced oxidative stress and TNF-α mediates activation of NF-κB signaling and YY1 upregulation, leading to repression of EAAT2. Thus, targeting reactive oxygen species (ROS), TNF-α and IKK-β may attenuate Mn-induced YY1 activation and consequent EAAT2 repression.

Original languageEnglish (US)
Pages (from-to)94-103
Number of pages10
JournalNeurotoxicology
Volume86
DOIs
StatePublished - Sep 2021

Keywords

  • EAAT2
  • Manganese
  • NF-κB
  • Oxidative stress
  • TNF-α
  • YY1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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