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Updated: Mar 13, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Blockade of Glutamine Synthetase Enhances Inflammatory Response in Microglial Cells
Erika M Palmieri1, Alessio Menga2, Aurore Lebrun3,4
11 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari , Bari, Italy .
Aims:
Microglial cells are brain-resident macrophages engaged in surveillance and maintained in a constant state of relative inactivity. However, their involvement in autoimmune diseases indicates that in pathological conditions microglia gain an inflammatory phenotype. The mechanisms underlying this change in the microglial phenotype are still unclear. Since metabolism is an important modulator of immune cell function, we focused our attention on glutamine synthetase (GS), a modulator of the response to lipopolysaccharide (LPS) activation in other cell types, which is expressed by microglia.
Results:
GS inhibition enhances release of inflammatory mediators of LPS-activated microglia in vitro, leading to perturbation of the redox balance and decreased viability of cocultured neurons. GS inhibition also decreases insulin-mediated glucose uptake in microglia. In vivo, microglia-specific GS ablation enhances expression of inflammatory markers upon LPS treatment. In the spinal cords from experimental autoimmune encephalomyelitis (EAE), GS expression levels and glutamine/glutamate ratios are reduced.
Innovation:
Recently, metabolism has been highlighted as mediator of immune cell function through the discovery of mechanisms that (behind these metabolic changes) modulate the inflammatory response. The present study shows for the first time a metabolic mechanism mediating microglial response to a proinflammatory stimulus, pointing to GS activity as a master modulator of immune cell function and thus unraveling a potential therapeutic target.
Conclusions:
Our study highlights a new role of GS in modulating immune response in microglia, providing insights into the pathogenic mechanisms associated with inflammation and new strategies of therapeutic intervention. Antioxid. Redox Signal. 26, 351-363.
Insights
Glutamine synthetase (GS) regulates microglial inflammatory responses. Inhibiting GS in microglia boosts inflammation and harms neurons, revealing GS as a therapeutic target for neuroinflammatory diseases.
Area of Science:
- Neuroimmunology
- Cellular Metabolism
- Neuroinflammation
Background:
- Microglia, the brain's immune cells, adopt inflammatory phenotypes in autoimmune diseases.
- Mechanisms driving microglial inflammatory activation are not fully understood.
- Metabolism significantly influences immune cell function, including microglia.
Purpose of the Study:
- Investigate the role of glutamine synthetase (GS) in modulating microglial inflammatory responses.
- Determine GS's impact on microglial activation and neuronal health.
- Explore GS as a potential therapeutic target for neuroinflammatory conditions.
Main Methods:
- In vitro studies using lipopolysaccharide (LPS)-activated microglia.
- In vivo experiments involving microglia-specific GS gene ablation.
- Analysis of spinal cord tissue from experimental autoimmune encephalomyelitis (EAE) models.
Main Results:
- GS inhibition in microglia increased inflammatory mediator release and neuronal damage.
- GS inhibition reduced insulin-mediated glucose uptake in microglia.
- Microglia-specific GS ablation exacerbated inflammatory markers upon LPS stimulation.
- Reduced GS expression and altered glutamine/glutamate ratios were observed in EAE spinal cords.
Conclusions:
- GS activity is a key regulator of microglial inflammatory responses to proinflammatory stimuli.
- This study identifies a novel metabolic mechanism controlling microglial immune function.
- Targeting GS offers a potential therapeutic strategy for neuroinflammatory diseases.
