Microglial Voltage-Gated Proton Channel Hv1 in Ischemic Stroke

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.