ArticleExperimental neurology2012
System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo.
Article in Experimental neurology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
45 citing papers in PubMed, 63 citations in OpenAlex.
- The therapeutic effect of N-acetylcysteine as an add-on to methadone maintenance therapy medication in outpatients with substance use disorders: A randomized, double-blind, placebo-controlled clinical trial.Brain and behavior · 2023Trial
- Immune-mediated excitotoxicity in brain disorders.Nature reviews. Immunology · 2026Review
- From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.Frontiers in molecular neuroscience · 2026Review
- Neuron-Glia Crosstalk in the Regulation of Astrocytic Antioxidative Mechanisms Following CNS Injury.Antioxidants (Basel, Switzerland) · 2025Review
- Intact corticostriatal function in aged system xTranslational psychiatry · 2025Article
- Role of the Intestinal Microbiota in the Molecular Pathogenesis of Atypical Parkinsonian Syndromes.International journal of molecular sciences · 2025Review
- System Xc-pathway as a potential regulatory target in neurological disorders.Frontiers in pharmacology · 2025Review
- Design, synthesis, and characterization of novel system xJournal of neuroinflammation · 2023Article
- Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics.Journal of neuroinflammation · 2022Review
- Cystine-glutamate antiporter deletion accelerates motor recovery and improves histological outcomes following spinal cord injury in mice.Scientific reports · 2021Article
- New concepts in the development of schizophrenia, autism spectrum disorders, and degenerative brain diseases based on chronic inflammation: A working hypothesis from continued advances in neuroscience research.Surgical neurology international · 2021Review
- TGFβ3 is neuroprotective and alleviates the neurotoxic response induced by aligned poly-l-lactic acid fibers on naïve and activated primary astrocytes.Acta biomaterialia · 2020Article
- IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis.Journal of neuroinflammation · 2020Article
- System xScientific reports · 2019Article
- Exercise-Induced Changes to the Macrophage Response in the Dorsal Root Ganglia Prevent Neuropathic Pain after Spinal Cord Injury.Journal of neurotrauma · 2019Article
- Effect of N-acetyl cysteine (NAC) supplementation on positive and negative syndrome scale in schizophrenia: a systematic review and meta-analysis of randomised controlled trials.European journal of clinical pharmacology · 2019Review
- Gut Inflammation in Association With Pathogenesis of Parkinson's Disease.Frontiers in molecular neuroscience · 2019Review
- Glial Cells Shape Pathology and Repair After Spinal Cord Injury.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2018Review
- Immune-based strategies for mood disorders: facts and challenges.Expert review of neurotherapeutics · 2018Review
- Intraspinal TLR4 activation promotes iron storage but does not protect neurons or oligodendrocytes from progressive iron-mediated damage.Experimental neurology · 2017Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.