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Translational Stroke Research

, Volume 5, Issue 1, pp 99–108 | Cite as

Microglial Voltage-Gated Proton Channel Hv1 in Ischemic Stroke

  • Long-Jun Wu
Original Article

Abstract

Microglia, resident immune cells in the brain, contribute both to the damage and resolution of ischemic stroke. However, the mechanisms of microglia's detrimental or beneficial role in the disease are poorly understood. The voltage-gated proton channel, Hv1, rapidly removes protons from depolarized cytoplasm, and is highly expressed in the immune system. In the brain, Hv1 is selectively and functionally expressed in microglia but not neurons. Although the physiological function of microglial Hv1 is still not clear, Hv1 is one of major ion channels expressed in resting microglia. Under pathological conditions, microglial Hv1 is required for NADPH oxidase (NOX)-dependent generation of reactive oxygen species (ROS) by providing charge compensation for exported electrons and relieving intracellular acidosis. In a mouse model of cerebral middle artery occlusion, Hv1 knockout mice are protected from ischemic damage, showing reduced NOX-dependent ROS production, microglial activation and neuronal cell death. Therefore, microglial Hv1 aids in NOX-dependent ROS generation, which subsequently induces neuronal cell death and a significant fraction of brain damage after ischemic stroke. These studies illuminate a critical role of microglial Hv1 in ischemic brain injury, providing a rationale for Hv1 as a potential therapeutic target for the treatment of ischemic stroke. The current understanding of Hv1 in ischemic injury through NOX-dependent ROS production may serve as a common model to reveal the deleterious role of microglia in neurological diseases other than ischemic stroke, such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, and neuropathic pain.

Keywords

Microglia Voltage-gated proton channel Hv1 NADPH oxidase Reactive oxygen species Sodium-proton exchanger Acid-sensing ion channels Ischemic stroke 

Notes

Acknowledgments

I thank Dr. David Clapham (Harvard Medical School) and Wu Lab members (Rutgers University) for critical reading of this manuscript. This work is supported by Scientist Development Grant from American Heart Association (11SDG7340011) and a start-up fund from Rutgers University to L.-J. W.

Conflict of Interest

Long-Jun Wu declares that he has no conflict of interest.

Compliance with Ethics Requirements

All institutional and national guidelines for the care and use of laboratory animals were followed.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Cell Biology and NeuroscienceRutgers UniversityPiscatawayUSA

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