title: IL-17 signalling in astrocytes promotes glutamate excitotoxicity: Indications for the link between inflammatory and neurodegenerative events in multiple sclerosis.
abstract: OBJECTIVE
  Th-17 cells have been exclusively referred to inflammatory events in multiple sclerosis (MS), while their importance in the development of glutamate excitotoxicity and the consequent neurodegeneration has been a completely unexplored concept. Accordingly, the objective of our study was to assess IL-17A effect on astrocyte ability to metabolize and release glutamate, considering that astrocytes had the central role in glutamate homeostasis.
  
  
  METHODS
  By using primary rat astrocyte cultures, astrocyte ability to uptake glutamate was estimated by the alterations of glutamate transporters (GLAST and GLT-1) expression, whereas changes in glutamine synthetase expression were used to estimate the ability to metabolize glutamate. Gene expression was determined by real time polymerase chain reaction (rtPCR). IL-17A effect on astrocyte ability to produce glutamate was investigated directly, by measuring the level of released glutamate using high performance liquid chromatography (HPLC).
  
  
  RESULTS
  Lower concentrations of IL-17A reduced the expressions of both glutamate transporters and glutamine synthetase; however, this effect was lost when IL-17A was applied in a higher dose. IL-17A did not significantly modify glutamate release from astrocyte in basal conditions, but following Ca2+stimulation, as well as Ca2+removal from the culture medium, IL-17A stimulated glutamate release in dose-dependent manner.
  
  
  CONCLUSIONS
  Together, these results support that IL-17A could promote glutamate excitotoxicity by decreasing astrocyte ability to uptake and convert glutamate to non-toxic glutamine, but also by stimulating Ca2+dependent glutamate release. Such interactions between IL-17A and glutamate excitotoxicity implicate the potential link between inflammation and neurodegeneration during MS pathogenesis, and identify astrocytes as a potential target in achieving neuroprotective effects in MS.
authors.affiliation: Department of Immunology, Medical Faculty, University of Nis, Blvd. dr Zorana Djindjica 81, 18000 Nis, Serbia. Electronic address: milosh.kostic@hotmail.com.
authors.forename: Milos
authors.initials: M
authors.lastname: Kostic
authors.affiliation: Department of Pathology, Medical Faculty, University of Nis, Blvd. dr Zorana Djindjica 81, 18000 Nis, Serbia.
authors.forename: Nikola
authors.initials: N
authors.lastname: Zivkovic
authors.affiliation: Clinic of Oncology, Clinical Center Nis, Blvd. dr Zorana Djindjica 48, 18000 Nis, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Cvetanovic
authors.affiliation: Department of Biochemistry, Medical Faculty, University of Nis, Blvd. dr Zorana Djindjica 81, 18000 Nis, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Stojanovic
authors.affiliation: Department of Immunology, Medical Faculty, University of Nis, Blvd. dr Zorana Djindjica 81, 18000 Nis, Serbia.
authors.forename: Miodrag
authors.initials: M
authors.lastname: Colic
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D002478:Cells, Cultured; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity*; D009103:Multiple Sclerosis / Q000276:immunology; D009410:Nerve Degeneration; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D002413:Cations, Divalent; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D011994:Recombinant Proteins; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat; D018698:Glutamic Acid; D002118:Calcium
keywords: Astrocyte; Glutamate excitotoxicity; Glutamate exocytosis; Glutamate transporter; Glutamine synthetase; IL-17A; Multiple sclerosis