title: Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation.
abstract: BACKGROUND
  Astrocytes respond to local insults within the brain and the spinal cord with important changes in their phenotype. This process, overall known as "activation", is observed upon proinflammatory stimulation and leads astrocytes to acquire either a detrimental phenotype, thereby contributing to the neurodegenerative process, or a protective phenotype, thus supporting neuronal survival. Within the mechanisms responsible for inflammatory neurodegeneration, oxidative stress plays a major role and has recently been recognized to be heavily influenced by changes in cytosolic iron levels. In this work, we investigated how activation affects the competence of astrocytes to handle iron overload and the ensuing oxidative stress.
  
  
  METHODS
  Cultures of pure cortical astrocytes were preincubated with proinflammatory cytokines (interleukin-1β and tumor necrosis factor α) or conditioned medium from lipopolysaccharide-activated microglia to promote activation and then exposed to a protocol of iron overload.
  
  
  RESULTS
  We demonstrate that activated astrocytes display an efficient protection against iron-mediated oxidative stress and cell death. Based on this evidence, we performed a comprehensive biochemical and molecular analysis, including a transcriptomic approach, to identify the molecular basis of this resistance.
  
  
  CONCLUSIONS
  We propose the protective phenotype acquired after activation not to involve the most common astrocytic antioxidant pathway, based on the Nrf2 transcription factor, but to result from a complex change in the expression and activity of several genes involved in the control of cellular redox state.
authors.forename: Romina
authors.initials: R
authors.lastname: Macco
authors.forename: Ilaria
authors.initials: I
authors.lastname: Pelizzoni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Consonni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Vitali
authors.forename: Giacomo
authors.initials: G
authors.lastname: Giacalone
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli Boneschi
authors.forename: Franca
authors.initials: F
authors.lastname: Codazzi
authors.affiliation: Division of Neuroscience, Dibit, San Raffaele Scientific Institute, via Olgettina 58, 20132, Milano, Italy. grohovaz.fabio@hsr.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grohovaz
authors.forename: Daniele
authors.initials: D
authors.lastname: Zacchetti
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D015153:Blotting, Western; D007501:Iron / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010641:Phenotype; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D007501:Iron