Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury
AuthorRitzel, Rodney M
Stoica, Bogdan A
Faden, Alan I
PublisherJohn Wiley and Sons Inc.
MetadataShow full item record
AbstractAcidosis is among the least studied secondary injury mechanisms associated with neurotrauma. Acute decreases in brain pH correlate with poor long-term outcome in patients with traumatic brain injury (TBI), however, the temporal dynamics and underlying mechanisms are unclear. As key drivers of neuroinflammation, we hypothesized that microglia directly regulate acidosis after TBI, and thereby, worsen neurological outcomes. Using a controlled cortical impact model in adult male mice we demonstrate that intracellular pH in microglia and extracellular pH surrounding the lesion site are significantly reduced for weeks after injury. Microglia proliferation and production of reactive oxygen species (ROS) were also increased during the first week, mirroring the increase in extracellular ROS levels seen around the lesion site. Microglia depletion by a colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622, markedly decreased extracellular acidosis, ROS production, and inflammation in the brain after injury. Mechanistically, we identified that the voltage-gated proton channel Hv1 promotes oxidative burst activity and acid extrusion in microglia. Compared to wildtype controls, microglia lacking Hv1 showed reduced ability to generate ROS and extrude protons. Importantly, Hv1-deficient mice exhibited reduced pathological acidosis and inflammation after TBI, leading to long-term neuroprotection and functional recovery. Our data therefore establish the microglial Hv1 proton channel as an important link that integrates inflammation and acidosis within the injury microenvironment during head injury. © 2020 The Authors.
Rights/Terms© 2020 The Authors. GLIA published by Wiley Periodicals LLC.
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/13979
- The voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation.
- Authors: Li Y, Ritzel RM, He J, Cao T, Sabirzhanov B, Li H, Liu S, Wu LJ, Wu J
- Issue date: 2021 Jan
- Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits.
- Authors: Henry RJ, Ritzel RM, Barrett JP, Doran SJ, Jiao Y, Leach JB, Szeto GL, Wu J, Stoica BA, Faden AI, Loane DJ
- Issue date: 2020 Apr 1
- The voltage-gated proton channel Hv1 contributes to neuronal injury and motor deficits in a mouse model of spinal cord injury.
- Authors: Murugan M, Zheng J, Wu G, Mogilevsky R, Zheng X, Hu P, Wu J, Wu LJ
- Issue date: 2020 Oct 20
- Deficiency in the voltage-gated proton channel Hv1 increases M2 polarization of microglia and attenuates brain damage from photothrombotic ischemic stroke.
- Authors: Tian DS, Li CY, Qin C, Murugan M, Wu LJ, Liu JL
- Issue date: 2016 Oct
- Hv1 proton channel facilitates production of ROS and pro-inflammatory cytokines in microglia and enhances oligodendrocyte progenitor cells damage from oxygen-glucose deprivation in vitro.
- Authors: Yu Y, Yu Z, Xie M, Wang W, Luo X
- Issue date: 2018 Mar 25