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Updated: May 5, 2026
Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
Published on: September 4, 2013
Mechanism of KDM4A in Regulating Microglial Polarization in Ischemic Stroke
Jingliang Du1, Xianyang Liang1, Denghui Wang1
1Department of Neurology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, No. 24, Jinghua Road, Jianxi District, Luoyang, 471003, Henan Province, China.
Abstract:
Microglia polarization plays important roles in inflammatory processes after ischemic stroke. This study aimed to explore the mechanism of lysine-specific histone demethylase 4 (KDM4A) in microglia polarization after ischemic stroke. The mouse model was established using middle cerebral artery occlusion/reperfusion (MCAO/R) and the cell model was established by oxygen-glucose deprivation/reperfusion (OGD/R). The neurological deficits and brain tissue injury were evaluated. The biomarkers of microglia were determined. Levels of KDM4A/mouse double minute-2 homolog (MDM2)/C1q/TNF-related protein-3 (CTRP3) were measured. Inflammatory cytokines were quantified. The impact of KDM4A on microglia polarization was assessed. The enrichment of KDM4A or histone 3 lysine 9 trimethylation (H3K9me3) on the MDM2 promoter was analyzed. The ubiquitination and protein levels of CTRP3 after MG132 and cycloheximide treatment were determined. Results showed that KDM4A and MDM2 were upregulated while CTRP3 was downregulated. KDM4A downregulation alleviated neurological dysfunction, rescued motor capacity, reduced inflammatory infiltration, suppressed microglia activation, and promoted M2 polarization. KDM4A inhibited the enrichment of H3K9me3 on the MDM2 promoter, increasing MDM2 expression and downregulating CTRP3 expression via ubiquitination and degradation. MDM2 overexpression or CTRP3 downregulation averted the promotive role of silencing KDM4A in microglia polarization. In conclusion, KDM4A promotes microglia polarization to aggravate ischemic stroke via the MDM2/CTRP3 axis.
Insights
Lysine-specific histone demethylase 4 (KDM4A) promotes harmful microglia polarization after ischemic stroke by regulating the MDM2/CTRP3 pathway, worsening brain injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Microglia polarization is critical in ischemic stroke inflammation.
- Understanding the molecular mechanisms driving microglia polarization is essential for developing targeted therapies.
Purpose of the Study:
- To investigate the role of lysine-specific histone demethylase 4A (KDM4A) in microglia polarization following ischemic stroke.
- To elucidate the underlying molecular mechanism involving mouse double minute-2 homolog (MDM2) and C1q/TNF-related protein-3 (CTRP3).
Main Methods:
- Established mouse (MCAO/R) and cell (OGD/R) models of ischemic stroke.
- Assessed neurological deficits, brain injury, microglia activation, and polarization markers.
- Quantified KDM4A, MDM2, CTRP3 levels, inflammatory cytokines, and histone modifications (H3K9me3).
- Investigated KDM4A's effect on MDM2 promoter enrichment and CTRP3 ubiquitination/degradation.
Main Results:
- KDM4A and MDM2 were upregulated, while CTRP3 was downregulated post-stroke.
- KDM4A inhibition improved neurological function, reduced inflammation, and promoted beneficial M2 microglia polarization.
- KDM4A suppressed H3K9me3 on the MDM2 promoter, increasing MDM2 and decreasing CTRP3 via degradation.
- MDM2 overexpression or CTRP3 knockdown mimicked KDM4A's pro-inflammatory effects.
Conclusions:
- KDM4A drives pro-inflammatory microglia polarization in ischemic stroke.
- The KDM4A/MDM2/CTRP3 axis represents a novel therapeutic target for mitigating ischemic stroke damage.
