System xc- activity and astrocytes are necessary for interleukin-1β-mediated hypoxic neuronal injury

Birgit Fogal, Jun Li, Doug Lobner, Louise D. McCullough, Sandra J. Hewett

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

The purpose of this study was to elucidate the cellular/biochemical pathway(s) by which interleukin-1β (IL-1β) contributes to the pathogenesis of hypoxic-ischemic brain damage. In vivo, IL-1 receptor type I (IL-1RI)-deficient mice showed smaller infarcts and less neurological deficits than wild-type animals after a 90 min reversible middle cerebral artery occlusion. In vitro, IL-1β mediated an enhancement of hypoxic neuronal injury in murine cortical cultures that was lacking in cultures derived from IL-1RI null mutant animals and was blocked by the IL-1 receptor antagonist or an IL-1RI blocking antibody. This IL-1β-mediated potentiation of hypoxic neuronal injury was associated with an increase in both cellular cystine uptake ([cystine]i) and extracellular glutamate levels ([glutamate] e) and was prevented by either ionotropic glutamate receptor antagonism or removal of L-cystine, suggesting a role for the cystine/glutamate antiporter (System xc-). Indeed, dual System xx c-/metabotropic glutamate receptor subunit 1 (mGluR1) antagonism but not selective mGluR1 antagonism prevented neuronal injury. Additionally, cultures derived from mGluR1-deficient mice exhibited the same potentiation in injury after treatment with IL-1β as wild-type cultures, an effect prevented by System xxc-/mGluR1 antagonism. Finally, assessment of System xc- function and kinetics in IL-1β-treated cultures revealed an increase in velocity of cystine transport (Vmax), in the absence of a change in affinity (K m). Neither the enhancement in [cystine]i, [glutamate]e, or neuronal injury were observed in chimeric cultures consisting of IL-1RI+/+ neurons plated on top of IL-1RI-/- astrocytes, highlighting the importance of astrocytemediated alterations in System xc- as a novel contributor to the development and progression of hypoxic neuronal injury.

Original languageEnglish (US)
Pages (from-to)10094-10105
Number of pages12
JournalJournal of Neuroscience
Volume27
Issue number38
DOIs
StatePublished - Sep 19 2007

    Fingerprint

Keywords

  • Astrocytes
  • Excitotoxicity
  • Hypoxia
  • IL-1 receptor type I
  • Interleukin-1β
  • System x

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this