Unconventional role of voltage‐gated proton channels (VSOP/Hv1) in regulation of microglial ROS production. Issue 5 (20th July 2017)

• Record Type: Journal Article
• Authors: Kawai, Takafumi; Okochi, Yoshifumi; Ozaki, Tomohiko; Imura, Yoshio; Koizumi, Schuichi; Yamazaki, Maya; Abe, Manabu; Sakimura, Kenji; Yamashita, Toshihide; Okamura, Yasushi
• Is Part Of: Journal of neurochemistry. Volume 142:Issue 5(2017)
• Page Start: 686
• Page End: 699
• Publication Date: 2017-07-20
• Subjects: aging -- brain ischemia -- microglia -- ROS -- voltage‐gated proton channel; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14106
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract : Voltage gated proton channel (VSOP/Hv1) has been believed to support reactive oxygen species (ROS) production in microglia. We found that VSOP/Hv1 has also paradoxical suppressive role in microglial ROS production possibly by changing actin dynamics. We also suggested that neuroprotective effect of VSOP/Hv1 deficiency on infarct volume in brain ischemia depends on the age of animals. Abstract: 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 .2010 ) and antibody production in B lymphocytes (Capasso et al .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 .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.