title: Deficiency in the voltage-gated proton channel Hv1 increases M2 polarization of microglia and attenuates brain damage from photothrombotic ischemic stroke.
abstract: Microglia become activated during cerebral ischemia and exert pro-inflammatory or anti-inflammatory role dependent of microglial polarization. NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production in microglia plays an important role in neuronal damage after ischemic stroke. Recently, NOX and ROS are consistently reported to participate in the microglial activation and polarization; NOX2 inhibition or suppression of ROS production are shown to shift the microglial polarization from M1 toward M2 state after stroke. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. However, the effect of Hv1 proton channel on microglial M1/M2 polarization state after cerebral ischemia remains unknown. In this study, we investigated the role of microglial Hv1 proton channel in modulating microglial M1/M2 polarization during the pathogenesis of ischemic cerebral injury using a mouse model of photothrombosis. Following photothrombotic ischemic stroke, wild-type mice presented obvious brain infarct, neuronal damage, and impaired motor coordination. However, mice lacking Hv1 (Hv1(-/-)) were partially protected from brain damage and motor deficits compared to wild-type mice. These rescued phenotypes in Hv1(-/-) mice in ischemic stroke is accompanied by reduced ROS production, shifted the microglial polarization from M1 to M2 state. Hv1 deficiency was also found to shift the M1/M2 polarization in primary cultured microglia. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent generation of reactive oxygen species (ROS) in the brain. ROS participate in microglial activation and polarization. However, the effect of Hv1 on microglial M1/M2 polarization state after cerebral ischemia remains unknown. Hv1 deficiency was found to shift the microglial polarization from M1 to M2 state in ischemic stroke accompanied by reduced ROS production. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke.
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dai-Shi
authors.initials: DS
authors.lastname: Tian
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Qin
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Madhuvika
authors.initials: M
authors.lastname: Murugan
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey, USA. lwu@dls.rutgers.edu.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. junli78@foxmail.com.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Liu
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D020520:Brain Infarction / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D016764:Cell Polarity / Q000235:genetics; D020767:Intracranial Thrombosis / Q000235:genetics* / Q000473:pathology*; D007473:Ion Channels / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000235:genetics* / Q000473:pathology*
chemical_list: D000963:Antimetabolites; C540876:Hv1 proton channel, mouse; D007473:Ion Channels; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D001973:Bromodeoxyuridine
keywords: ischemic stroke; microglia; photothrombosis; polarization; voltage-gated proton channel Hv1