title: Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage.
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.
authors.affiliation: Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Junli
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey, USA.|Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Daishi
authors.initials: D
authors.lastname: Tian
authors.affiliation: Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Madhuvika
authors.initials: M
authors.lastname: Murugan
authors.affiliation: Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Ukpong B
authors.initials: UB
authors.lastname: Eyo
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Cheryl F
authors.initials: CF
authors.lastname: Dreyfus
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000633:toxicity*; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D017382:Reactive Oxygen Species
chemical_list: D002614:Chelating Agents; C540876:Hv1 proton channel, mouse; D007473:Ion Channels; D004676:Myelin Basic Protein; D017382:Reactive Oxygen Species; D003471:Cuprizone; D019255:NADPH Oxidases
keywords: cuprizone; demyelination; microglia; multiple sclerosis; oligodendrocytes; voltage-gated proton channel Hv1