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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglial forkhead box O3a deficiency attenuates LPS-induced neuro-inflammation and depressive-like behaviour
Rikang Wang1, Lianru Ji2, Shun Yuan2
1Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China.
Background And Purpose:
Depression is closely linked with microglial activation and neuro-inflammation. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood-relevant behaviour. However, little is known about the inflammatory mechanisms of in the microglia of the brain. Here, we have investigated the role of microglial FOXO3a/PPAR-γ in the development of depression.
Experimental Approach:
The effect of FOXO3a on microglia inflammation was analysed in vitro and in lipopolysaccharide (LPS)-induced depression-like behaviours in vivo. ChIP-seq and Dual-luciferase reporter assays were used to confirm the interaction between FOXO3a and PPAR-γ. Behavioural changes were measured, while inflammatory cytokines, microglial phenotype and morphological properties were determined by ELISA, qRT-PCR, western blotting and immunostaining.
Key Results:
Overexpression of FOXO3a significantly attenuated expression of PPAR-γ and enhanced the microglial polarization towards the M1 phenotype, while knockdown of FOXO3a had the opposite effect. FOXO3a binds to the promoters of PPAR-γ and decreases its transcription activity. Importantly, deacetylation and activation of FOXO3a regulate LPS-induced neuro-inflammation by inhibiting the expression of PPAR-γ in microglia cells, supporting the antidepressant potential of histone deacetylase inhibitors. Microglial FOXO3a deficiency in mice alleviated LPS-induced neuro-inflammation and depression-like behaviours but failed to reduce anxiety behaviour, whereas pharmacological inhibition of PPAR-γ by GW9662 restored LPS-induced microglial activation and depressive-like behaviours in microglial FOXO3a-deficient mice.
Conclusion And Implications:
FOXO3a/PPAR-γ axis plays an important role in microglial activation and depression, identifying a new therapeutic avenue for the treatment of major depression.
Insights
Forkhead box (FOX) O3a regulates microglial inflammation by inhibiting peroxisome proliferator-activated receptor-γ (PPAR-γ), offering a new therapeutic target for depression.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Depression is linked to microglial activation and neuro-inflammation.
- Peroxisome proliferator-activated receptor-γ (PPAR-γ) is crucial for M2 microglial activation.
- Forkhead box (FOX) O3a influences mood-related behaviors, but its role in microglial inflammation is unclear.
Purpose of the Study:
- To investigate the role of microglial FOXO3a/PPAR-γ axis in depression.
- To elucidate the inflammatory mechanisms involving FOXO3a in brain microglia.
Main Methods:
- In vitro and in vivo studies using lipopolysaccharide (LPS)-induced depression models.
- Chromatin immunoprecipitation sequencing (ChIP-seq) and dual-luciferase reporter assays to confirm FOXO3a-PPAR-γ interaction.
- Analysis of behavioral changes, inflammatory cytokines, microglial phenotype, and morphology.
Main Results:
- FOXO3a overexpression attenuated PPAR-γ expression and promoted M1 microglial polarization; FOXO3a knockdown had opposite effects.
- FOXO3a directly binds to PPAR-γ promoters, inhibiting its transcription.
- FOXO3a activation reduced LPS-induced neuro-inflammation and depression-like behaviors in mice, while PPAR-γ inhibition reversed these effects in FOXO3a-deficient mice.
Conclusions:
- The FOXO3a/PPAR-γ axis is a key regulator of microglial activation and depression.
- Targeting this axis presents a novel therapeutic strategy for major depression.
- Histone deacetylase inhibitors show potential for treating depression via FOXO3a activation.
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