Depletion of Microglia Attenuates Dendritic Spine Loss and Neuronal Apoptosis in the Acute Stage of Moderate Traumatic Brain Injury in Mice

Wang, Chuanfang; Zhao, Chengcheng; Liu, Wenlan; Huang, Xianjian; Deng, Yuefei; Jiang, Jiyao; Li, Weiping

doi:10.1089/neu.2019.6460

Cited by 36 publications

(26 citation statements)

References 53 publications

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“…43,44,48,49 Increasing evidence show that microglia polarize into a variety of phenotypes at different stages of injuries in CNS. 50,51 Decreased expression of Arg1 in STAT6 −/− microglia/macrophages led to impairments in phagocytosis and loss of anti-inflammatory modality which indicates that microglia phenotype is closely related to phagocytosis. 52 Direct evidence for the relationship between specific microglia phenotype and phagocytosis should be investigated in the future.…”

Section: Fifth Mrs2578 Treatment Exacerbated the Results Of Mnss Andmentioning

confidence: 99%

“…53 Microglia and macrophages are immune cells in the brain and play a role in the inflammation response after brain injury. 3,50,54 In response to brain injury, microglia promptly acquire properties of reactive species generation, antigen presentation, phagocytosis, and the production of inflammatory mediators including IL-1, TNFα, and IL-6. 55 Proinflammatory cytokines released by necrotic cells induce subsequent neutrophil infiltration to ischemic tissue.…”

Section: Fifth Mrs2578 Treatment Exacerbated the Results Of Mnss Andmentioning

confidence: 99%

“…The balance between different microglial phenotypes could affect regenerative therapies after CNS injury . Increasing evidence show that microglia polarize into a variety of phenotypes at different stages of injuries in CNS . Decreased expression of Arg1 in STAT6 −/− microglia/macrophages led to impairments in phagocytosis and loss of anti‐inflammatory modality which indicates that microglia phenotype is closely related to phagocytosis .…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation also affects the neurological function after injury . Microglia and macrophages are immune cells in the brain and play a role in the inflammation response after brain injury . In response to brain injury, microglia promptly acquire properties of reactive species generation, antigen presentation, phagocytosis, and the production of inflammatory mediators including IL‐1, TNF‐α, and IL‐6 .…”

Section: Discussionmentioning

confidence: 99%

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P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

et al. 2020

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Introduction Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown. Aim To investigate whether P2Y6 receptor‐mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke. Results The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL‐1α, IL‐1β, IL‐6, IL‐10, TNF‐α, TGF‐β, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor‐mediated phagocytosis. Conclusion Our results indicate that P2Y6 receptor‐mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.

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Section: Fifth Mrs2578 Treatment Exacerbated the Results Of Mnss Andmentioning

confidence: 99%

Section: Fifth Mrs2578 Treatment Exacerbated the Results Of Mnss Andmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

et al. 2020

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“…Some studies documented the destructive role of microglia/macrophages in brain pathologies as highly activated microglia release a plethora of neurotoxic factors, including inflammatory cytokines, chemokines, and free radicals. In support of this view, microglia depletion has been reported to result in neuroprotection in experimental models of hemorrhagic stroke, chronic cerebral hypoperfusion, traumatic brain injury (TBI), and Alzheimer's disease (AD) . In contrast, quite a few studies documented that the removal of microglia enhanced neuroinflammation and thus exacerbated the neurological deficits after brain injuries or neurodegenerations, suggesting beneficial roles of microglia in the presence of CNS pathologies .…”

mentioning

confidence: 98%

Microglia/macrophage diversities in central nervous system physiology and pathology

Xie

2019

CNS Neurosci Ther

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Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury

Ritzel

et al. 2020

Glia

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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.

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Depletion of Microglia Attenuates Dendritic Spine Loss and Neuronal Apoptosis in the Acute Stage of Moderate Traumatic Brain Injury in Mice

Cited by 36 publications

References 53 publications

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

Microglia/macrophage diversities in central nervous system physiology and pathology

Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury

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