title: System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo.
abstract: It is widely believed that microglia and monocyte-derived macrophages (collectively referred to as central nervous system (CNS) macrophages) cause excitotoxicity in the diseased or injured CNS. This view has evolved mostly from in vitro studies showing that neurotoxic concentrations of glutamate are released from CNS macrophages stimulated with lipopolysaccharide (LPS), a potent inflammogen. We hypothesized that excitotoxic killing by CNS macrophages is more rigorously controlled in vivo, requiring both the activation of the glutamate/cystine antiporter (system x(c)(-)) and an increase in extracellular cystine, the substrate that drives glutamate release. Here, we show that non-traumatic microinjection of low-dose LPS into spinal cord gray matter activates CNS macrophages but without causing overt neuropathology. In contrast, neurotoxic inflammation occurs when LPS and cystine are co-injected. Simultaneous injection of NBQX, an antagonist of AMPA glutamate receptors, reduces the neurotoxic effects of LPS+cystine, implicating glutamate as a mediator of neuronal cell death in this model. Surprisingly, neither LPS nor LPS+cystine adversely affects survival of oligodendrocytes or oligodendrocyte progenitor cells. Ex vivo analyses show that redox balance in microglia and macrophages is controlled by induction of system x(c)(-) and that high GSH:GSSG ratios predict the neurotoxic potential of these cells. Together, these data indicate that modulation of redox balance in CNS macrophages, perhaps through regulating system x(c)(-), could be a novel approach for attenuating injurious neuroinflammatory cascades.
authors.affiliation: Center for Brain and Spinal Cord Repair, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Kigerl
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Ankeny
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Garg
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Zhen
authors.initials: Z
authors.lastname: Guan
authors.forename: Wenmin
authors.initials: W
authors.lastname: Lai
authors.forename: Dana M
authors.initials: DM
authors.lastname: McTigue
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
mesh_terms: D000818:Animals; D003553:Cystine / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D061346:Laser Capture Microdissection / Q000379:methods; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D013118:Spinal Cord Diseases / Q000139:chemically induced* / Q000473:pathology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D003553:Cystine; D005978:Glutathione
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