Abstract
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. 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. 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. 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.
Highlights
Microglia are brain-resident macrophages involved in the maintenance of central nervous system (CNS) homeostasis by continually surveying the extracellular environment [10]
It is well established that brain microglia express the glutamate scavenging system known to be present in astrocytes, namely the cellular glutamate transporter GLT-1 and glutamine synthetase (GS) [12, 44, 69], in physiological and in pathological conditions [11, 28, 65]
The present work highlights for the first time the role of glutamate conversion to glutamine in modulating the ability of microglia to respond to the inflammatory stimulus
Summary
Microglia are brain-resident macrophages involved in the maintenance of central nervous system (CNS) homeostasis by continually surveying the extracellular environment [10]. Once microglia encounter a harmful or foreign entity, they enter an activated state, regulating CNS innate immunity and initiating appropriate responses. These events, often leading to neuroinflammation, have the sole purpose to protect the CNS; uncontrolled or prolonged neuroinflammation is potentially harmful and can result in cellular damage. This is relevant to neurodegenerative diseases, to which microglial activation and neuroinflammation have been associated [23, 59].
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