The voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation

Yun Li, Rodney M. Ritzel, Junyun He, Tuoxin Cao, Boris Sabirzhanov, Hui Li, Simon Liu, Long Jun Wu, Junfang Wu

Research output: Contribution to journalArticlepeer-review

Abstract

Tissue 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.

Original languageEnglish (US)
JournalBrain, Behavior, and Immunity
DOIs
StateAccepted/In press - 2020

Keywords

  • Acidosis
  • Hv1
  • Microglia
  • Motor function
  • Oxidative stress
  • Spinal cord injury
  • Voltage-gated proton channel

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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