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Updated: Aug 3, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglial SIX2 suppresses lipopolysaccharide (LPS)-induced neuroinflammation by up-regulating FXYD2 expression
Xia-Yin Cao1, Yi Liu1, Jia-Shuo Kan1
1Department of Neurobiology and Cellular biology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
Abstract:
Parkinson's disease (PD) is a severe neurodegenerative disease associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although its pathogenesis remains unclear, microglia-mediated neuroinflammation significantly contributes to the development of PD. Here we showed that the sine oculis homeobox (SIX) homologue family transcription factors SIX2 exerted significant effects on neuroinflammation. The SIX2 protein, which is silenced during development, was reactivated in lipopolysaccharide (LPS)-treated microglia. The reactivated SIX2 in microglia mitigated the LPS induced inflammatory effects, and then reduced the toxic effect of conditioned media (CM) of microglia on co-cultured MES23.5 DA cells. Using the LPS-stimulated Cx3cr1-CreERT2 mouse model, we also demonstrated that the highly-expressed SIX2 in microglia obviously attenuated neuroinflammation and protected the DA neurons in SN. Further RNA-Seq analysis on the inflammatory activated microglia revealed that the SIX2 exerted these effects via up-regulating the FXYD domain containing ion transport regulator 2 (FXYD2). Taken together, our study demonstrated that SIX2 was an endogenous anti-inflammatory factor in microglia, and it exerted anti-neuroinflammatory effects by regulating the expression of FXYD2, which provides new ideas for anti-neuroinflammation in PD.
Insights
Sine oculis homeobox homolog 2 (SIX2) is reactivated in microglia during inflammation, acting as an endogenous anti-inflammatory factor. SIX2 mitigates neuroinflammation and protects dopaminergic neurons, offering new therapeutic avenues for Parkinson
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Parkinson's disease (PD) involves dopaminergic neuron loss in the substantia nigra.
- Microglia-driven neuroinflammation is a key contributor to PD pathogenesis.
- The role of transcription factors in microglial inflammatory responses is under investigation.
Purpose of the Study:
- To investigate the role of sine oculis homeobox homolog 2 (SIX2) in microglial activation and neuroinflammation.
- To determine if SIX2 acts as an endogenous regulator of inflammatory responses in microglia.
- To explore the therapeutic potential of SIX2 in protecting dopaminergic neurons in Parkinson's disease models.
Main Methods:
- Investigated SIX2 expression in lipopolysaccharide (LPS)-stimulated microglia.
- Assessed the impact of SIX2 on LPS-induced inflammatory effects in microglia.
- Evaluated the protective effects of microglia conditioned media (CM) on co-cultured dopaminergic (DA) cells.
- Utilized a Cx3cr1-CreERT2 mouse model to study SIX2 function in vivo.
- Performed RNA-sequencing (RNA-Seq) analysis to identify SIX2-regulated genes.
Main Results:
- SIX2 protein, normally silenced, is reactivated in LPS-treated microglia.
- Reactivated SIX2 mitigates LPS-induced inflammatory effects in microglia.
- SIX2 reduces the toxicity of microglial CM on dopaminergic cells.
- In vivo studies show SIX2 attenuates neuroinflammation and protects DA neurons in the substantia nigra.
- RNA-Seq reveals SIX2 up-regulates FXYD domain containing ion transport regulator 2 (FXYD2) expression.
Conclusions:
- SIX2 functions as an endogenous anti-inflammatory factor in microglia.
- SIX2 exerts anti-neuroinflammatory effects by regulating FXYD2 expression.
- Targeting SIX2-FXYD2 pathway offers novel therapeutic strategies for Parkinson's disease.
