Autoantigen specific T cells inhibit glutamate uptake in astrocytes by decreasing expression of astrocytic glutamate transporter GLAST: a mechanism mediated by tumor necrosis factor-alpha

FASEB J. 2005 Nov;19(13):1878-80. doi: 10.1096/fj.05-3748fje. Epub 2005 Aug 25.

Abstract

Glutamate excitotoxicity is increasingly being recognized as a pathogenic mechanism in autoimmune inflammatory disorders of the central nervous system (CNS). Astrocytes are the predominant players in clearing the extracellular space from glutamate and normally have extensive spare capacities in terms of glutamate uptake. We asked what might be the basis of glutamate accumulation in T cell triggered autoimmune inflammation. In vitro, coculture of primary rat astrocytes with activated myelin basic protein (MBP)-specific T cells resulted in a decrease of astrocytic glutamate uptake rates (Vmax). In parallel, the amount of the Na+-dependent glutamate transporter GLAST was reduced within 48-60 h. Significant decreases of GLAST protein were observed in astrocytes harvested after incubation with T cells activated by MBP during coculture or after incubation with T cell blasts preactivated in the presence of splenocytes beforehand. Since exposure of astrocytes to cell-free supernatant of MBP-activated T cells also resulted in reduced expression of GLAST, a humoral factor appeared to be the driving agent. In blocking experiments using neutralizing antibodies and by incubation of astrocytes with recombinant cytokines, tumor necrosis factor-alpha (TNF-alpha) was identified as being responsible for the down-modulation of GLAST. GLAST was also down-regulated in the CNS of autoimmune encephalomyelitic rats but not in animals suffering from systemic inflammation. Since the loss of GLAST was not confined to inflammatory infiltrates, here too, a humoral factor seemed to be causative. In conclusion, T cell derived TNF-alpha impairs glutamate clearance capacity of astrocytes in vitro and probably also in vivo providing a pathogenic link to glutamate excitotoxicity that may contribute to early axonal dysfunction remote from active autoimmune inflammatory demyelination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System X-AG / metabolism
  • Amino Acid Transport System X-AG / physiology*
  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism*
  • Autoantigens / chemistry*
  • Binding Sites
  • Central Nervous System / embryology
  • Coculture Techniques
  • Cytokines / metabolism
  • Demyelinating Diseases / pathology
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Flow Cytometry
  • Glutamates / pharmacokinetics*
  • Immunoblotting
  • Inflammation
  • Kinetics
  • Models, Biological
  • Myelin Basic Protein / metabolism
  • Rats
  • Sodium / metabolism
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • Amino Acid Transport System X-AG
  • Autoantigens
  • Cytokines
  • Glutamates
  • Myelin Basic Protein
  • Tumor Necrosis Factor-alpha
  • Sodium