title: Blockade of Glutamine Synthetase Enhances Inflammatory Response in Microglial Cells.
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.
authors.affiliation: 1 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari , Bari, Italy .
authors.forename: Erika M
authors.initials: EM
authors.lastname: Palmieri
authors.affiliation: 2 National Cancer Research Center, Istituto Tumori 'Giovanni Paolo II,' Bari, Italy .
authors.forename: Alessio
authors.initials: A
authors.lastname: Menga
authors.affiliation: 3 Department of Cancer Biology, Thomas Jefferson University , Philadelphia, Pennsylvania.|4 Department of Neurological Surgery, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Aurore
authors.initials: A
authors.lastname: Lebrun
authors.affiliation: 3 Department of Cancer Biology, Thomas Jefferson University , Philadelphia, Pennsylvania.|4 Department of Neurological Surgery, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Hooper
authors.affiliation: 5 Department of Chemistry, University of Kentucky , Lexington, Kentucky.|6 Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: 7 Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, University of Leuven , Leuven, Belgium .|8 Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium .
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: 1 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari , Bari, Italy .|2 National Cancer Research Center, Istituto Tumori 'Giovanni Paolo II,' Bari, Italy .
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castegna
mesh_terms: D000818:Animals; D015415:Biomarkers; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D007328:Insulin; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D005974:Glutamate-Ammonia Ligase; D005947:Glucose
keywords: glutamine; glutamine synthetase; insulin resistance; microglia; neuroinflammation