Unconventional role of voltage‐gated proton channels ( VSOP /Hv1) in regulation of microglial ROS production

It has been established that voltage‐gated proton channels ( VSOP /Hv1), encoded by Hvcn1 , support reactive oxygen species ( ROS ) production in phagocytic activities of neutrophils (El Chemaly et al . [El Chemaly A., 2010]) and antibody production in B lymphocytes (Capasso et al . [Capasso M., 2010]). VSOP /Hv1 is a potential therapeutic target for brain ischemia, since Hvcn1 deficiency reduces microglial ROS production and protects brain from neuronal damage (Wu et al . [Wu L. J., 2012]). In the present study, we report that VSOP /Hv1 has paradoxical suppressive role in ROS production in microglia. Extracellular ROS production was lower in neutrophils of Hvcn1 −/− mice than WT mice as reported. In contrast, it was drastically enhanced in isolated Hvcn1 −/− microglia as compared with cells from WT mice. Actin dynamics was altered in Hvcn1 −/− microglia and intracellular distribution of cytosolic NADPH oxidase subunit, p67, was changed. When expression levels of oxidative stress responsive antioxidant genes were compared between WT and Hvcn1 −/− in cerebral cortex at different ages of animals, they were slightly decreased in Hvcn1 −/− mice at younger stage (1 day, 5 days, 3 weeks old), but drastically increased at aged stage (6 months old), suggesting that the regulation of microglial ROS production by VSOP /Hv1 is age‐dependent. We also performed brain ischemic stroke experiments and found that the neuroprotective effect of VSOP /Hv1deficiency on infarct volume depended on the age of animals. Taken together, regulation of ROS production by VSOP /Hv1 is more complex than previously thought and significance of VSOP /Hv1 in microglial ROS production depends on age.