Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage

Junli Liu, Daishi Tian, Madhuvika Murugan, Ukpong B. Eyo, Cheryl F. Dreyfus, Wei Wang, LongJun Wu

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production in inflammatory cells including microglia plays an important role in demyelination and free radical-mediated tissue injury in multiple sclerosis (MS). However, the mechanism underlying microglial ROS production and demyelination remains largely unknown. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. In the present study, we sought to determine the role of microglial Hv1 proton channels in a mouse model of cuprizone-induced demyelination, a model for MS. Following cuprizone exposure, wild-type mice presented obvious demyelination, decreased myelin basic protein expression, loss of mature oligodendrocytes, and impaired motor coordination in comparison to mice on a normal chow diet. However, mice lacking Hv1 (Hv1-/-) are partially protected from demyelination and motor deficits compared with those in wild-type mice. These rescued phenotypes in Hv1-/- mice in cuprizone-induced demyelination is accompanied by reduced ROS production, ameliorated microglial activation, increased oligodendrocyte progenitor cell (NG2) proliferation, and increased number of mature oligodendrocytes. These results demonstrate that the Hv1 proton channel is required for cuprizone-induced microglial oxidative damage and subsequent demyelination. Our study suggests that the microglial Hv1 proton channel is a unique target for controlling NOX-dependent ROS production in the pathogenesis of MS.

Original languageEnglish (US)
Pages (from-to)347-356
Number of pages10
JournalJournal of Neurochemistry
Volume135
Issue number2
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

Keywords

  • cuprizone
  • demyelination
  • microglia
  • multiple sclerosis
  • oligodendrocytes
  • voltage-gated proton channel Hv1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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