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Updated: Jan 3, 2026
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Microglial Hv1 proton channels promote white matter injuries after chronic hypoperfusion in mice
Ying Yu1, Xiang Luo1, Chunyu Li1
1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Microglia are critical in damage/repair processes during ischemic white matter injury (WMI). Voltage-gated proton channel (Hv1) is expressed in microglia and contributes to nicotinamide adenine dinucleotide phosphate oxidase complex-dependent production of reactive oxygen species (ROS). Recent findings have shown that Hv1 is involved in regulating luminal pH of M1-polarized microglial phagosomes and inhibits endocytosis in microglia. We previously reported that Hv1 facilitated production of ROS and pro-inflammatory cytokines in microglia and enhanced damage to oligodendrocyte progenitor cells from oxygen and glucose deprivation. To investigate the role of Hv1 in hypoperfusion-induced WMI, we employed mice that were genetically devoid of Hv1 (Hv1-/- ), as well as a model of subcortical vascular dementia via bilateral common carotid artery stenosis. Integrity of myelin was assessed using immunofluorescent staining and transmission electron microscopy, while cognitive impairment was assessed using an eight-arm radial maze test. Hv1 deficiency was found to attenuate bilateral common carotid artery stenosis-induced disruption of white matter integrity and impairment of working memory. Immunofluorescent staining and western blotting were used to assay changes in oligodendrocytes, OPCs, and microglial polarization. Compared with that in wild-type (WT) mice, Hv1-/- mice exhibited reduced ROS generation, decreased pro-inflammatory cytokines production, and an M2-dominant rather than M1-dominant microglial polarization. Furthermore, Hv1-/- mice exhibited enhanced OPC proliferation and differentiation into oligodendrocytes. Results of mouse-derived microglia-OPC co-cultures suggested that PI3K/Akt signaling was involved in Hv1-deficiency-induced M2-type microglial polarization and concomitant OPC differentiation. These results suggest that microglial Hv1 is a promising therapeutic target for reducing ischemic WMI and cognitive impairment.
Insights
Targeting the voltage-gated proton channel (Hv1) in microglia may reduce white matter injury and cognitive decline. Hv1 deficiency improved white matter integrity and memory in a mouse model of vascular dementia.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Microglia play key roles in brain damage and repair after ischemic white matter injury (WMI).
- Voltage-gated proton channel 1 (Hv1) in microglia influences reactive oxygen species (ROS) production and inflammatory responses.
- Previous studies indicated Hv1 exacerbates damage to oligodendrocyte progenitor cells (OPCs).
Purpose of the Study:
- To investigate the role of microglial Hv1 in hypoperfusion-induced WMI and associated cognitive impairment.
- To determine if Hv1 deficiency offers neuroprotection in a mouse model of vascular dementia.
Main Methods:
- Utilized Hv1-deficient (Hv1-/-) mice and a bilateral common carotid artery stenosis model.
- Assessed white matter integrity via immunofluorescence and electron microscopy.
- Evaluated cognitive function using an eight-arm radial maze test.
- Analyzed oligodendrocyte, OPC, and microglial polarization markers using immunofluorescence and Western blotting.
Main Results:
- Hv1 deficiency significantly attenuated WMI, preserved white matter integrity, and improved working memory.
- Hv1-/- mice showed reduced ROS generation and pro-inflammatory cytokine production.
- Microglial polarization shifted towards an M2-dominant phenotype in Hv1-/- mice, promoting OPC proliferation and differentiation.
- PI3K/Akt signaling pathway was implicated in Hv1-deficiency-mediated M2 polarization and OPC differentiation.
Conclusions:
- Microglial Hv1 contributes to ischemic white matter injury and cognitive deficits.
- Targeting microglial Hv1 presents a potential therapeutic strategy for mitigating WMI and cognitive impairment.
- Hv1 modulation influences microglial polarization and supports myelin repair processes.
