Blockade of Glutamine Synthetase Enhances Inflammatory Response in Microglial Cells

Erika M. Palmieri, Alessio Menga, Aurore Lebrun, Douglas C. Hooper, D. Allan Butterfield, Massimiliano Mazzone, Alessandra Castegna

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)351-363
Number of pages13
JournalAntioxidants and Redox Signaling
Volume26
Issue number8
DOIs
StatePublished - Mar 10 2017

Bibliographical note

Publisher Copyright:
© Copyright 2017, Mary Ann Liebert, Inc.

Keywords

  • glutamine
  • glutamine synthetase
  • insulin resistance
  • microglia
  • neuroinflammation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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