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dc.contributor.authorLi, Yun
dc.contributor.authorRitzel, Rodney M
dc.contributor.authorHe, Junyun
dc.contributor.authorCao, Tuoxin
dc.contributor.authorSabirzhanov, Boris
dc.contributor.authorLi, Hui
dc.contributor.authorLiu, Simon
dc.contributor.authorWu, Long-Jun
dc.contributor.authorWu, Junfang
dc.date.accessioned2020-10-20T13:50:13Z
dc.date.available2020-10-20T13:50:13Z
dc.date.issued2020-10-08
dc.identifier.urihttp://hdl.handle.net/10713/13903
dc.description.abstractTissue acidosis is an important secondary injury process in the pathophysiology of traumatic spinal cord injury (SCI). To date, no studies have examined the role of proton extrusion as mechanism of pathological acidosis in SCI. In the present study, we hypothesized that the phagocyte-specific proton channel Hv1 mediates hydrogen proton extrusion after SCI, contributing to increased extracellular acidosis and poor long-term outcomes. Using a contusion model of SCI in adult female mice, we demonstrated that tissue pH levels are markedly lower during the first week after SCI. Acidosis was most evident at the injury site, but also extended into proximal regions of the cervical and lumbar cord. Tissue reactive oxygen species (ROS) levels and expression of Hv1 were significantly increased during the week of injury. Hv1 was exclusively expressed in microglia within the CNS, suggesting that microglia contribute to ROS production and proton extrusion during respiratory burst. Depletion of Hv1 significantly attenuated tissue acidosis, NADPH oxidase 2 (NOX2) expression, and ROS production at 3 d post-injury. Nanostring analysis revealed decreased gene expression of neuroinflammatory and cytokine signaling markers in Hv1 knockout (KO) mice. Furthermore, Hv1 deficiency reduced microglia proliferation, leukocyte infiltration, and phagocytic oxidative burst detected by flow cytometry. Importantly, Hv1 KO mice exhibited significantly improved locomotor function and reduced histopathology. Overall, these data suggest an important role for Hv1 in regulating tissue acidosis, NOX2-mediated ROS production, and functional outcome following SCI. Thus, the Hv1 proton channel represents a potential target that may lead to novel therapeutic strategies for SCI. © 2020 The Authorsen_US
dc.description.urihttps://doi.org/10.1016/j.bbi.2020.10.005en_US
dc.language.isoenen_US
dc.publisherAcademic Press Inc.en_US
dc.relation.ispartofBrain, behavior, and immunityen_US
dc.rightsCopyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.en_US
dc.subjectAcidosisen_US
dc.subjectHv1en_US
dc.subjectMicrogliaen_US
dc.subjectMotor functionen_US
dc.subjectOxidative stressen_US
dc.subjectSpinal cord injuryen_US
dc.subjectVoltage-gated proton channelen_US
dc.titleThe voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation.en_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.bbi.2020.10.005
dc.identifier.pmid33039662
dc.source.countryNetherlands


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