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Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury
Author(s) -
Ritzel Rodney M.,
He Junyun,
Li Yun,
Cao Tuoxin,
Khan Niaz,
Shim Bosung,
Sabirzhanov Boris,
Aubrecht Taryn,
Stoica Bogdan A.,
Faden Alan I.,
Wu LongJun,
Wu Junfang
Publication year - 2021
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23926
Subject(s) - microglia , neuroinflammation , neuroprotection , traumatic brain injury , acidosis , inflammation , biology , extracellular , reactive oxygen species , neurodegeneration , oxidative stress , endocrinology , medicine , neuroscience , microbiology and biotechnology , immunology , disease , psychiatry
Acidosis 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.