| System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo. | |
| | |
MedLine Citation:
|
PMID: 22079587 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
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:
|
Kristina A Kigerl; Daniel P Ankeny; Sanjay K Garg; Ping Wei; Zhen Guan; Wenmin Lai; Dana M McTigue; Ruma Banerjee; Phillip G Popovich |
Related Documents
:
|
18184867 - Monocyte migration to inflamed skin and lymph nodes is differentially controlled by l-s... 11037977 - Monocyte:astrocyte interactions regulate mcp-1 expression in both cell types. 12095707 - Differentiation of the human monocyte cell line, u937, with dibutyryl cyclicamp induces... 20526747 - Study of the interaction of the c-reactive protein monomer with the u937 monocyte. 11859097 - The dendritic cell-specific adhesion receptor dc-sign internalizes antigen for presenta... 16406837 - Interaction of pathogenic mycobacteria with the host immune system. |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2011-11-4 |
Journal Detail:
|
Title: Experimental neurology Volume: - ISSN: 1090-2430 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
|
Created Date: 2011-11-14 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0370712 Medline TA: Exp Neurol Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
|
Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
|
Center for Brain and Spinal Cord Repair, College of Medicine, The Ohio State University, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barri...
Next Document: The central versus peripheral antinociceptive effects of ?-opioid receptor agonists in the new model...