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.
| Original language | English |
|---|---|
| Article number | 130 |
| Journal | Journal of Neuroinflammation |
| Volume | 10 |
| DOIs | |
| Publication status | Published - Oct 28 2013 |
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Keywords
- Astrocyte activation
- Cytokines
- Iron
- Microglia
- Nrf2
- Oxidative stress
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Neurology
- Immunology
- Neuroscience(all)
Cite this
Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation. / Macco, Romina; Pelizzoni, Ilaria; Consonni, Alessandra; Vitali, Ilaria; Giacalone, Giacomo; Martinelli Boneschi, Filippo; Codazzi, Franca; Grohovaz, Fabio; Zacchetti, Daniele.
In: Journal of Neuroinflammation, Vol. 10, 130, 28.10.2013.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation
AU - Macco, Romina
AU - Pelizzoni, Ilaria
AU - Consonni, Alessandra
AU - Vitali, Ilaria
AU - Giacalone, Giacomo
AU - Martinelli Boneschi, Filippo
AU - Codazzi, Franca
AU - Grohovaz, Fabio
AU - Zacchetti, Daniele
PY - 2013/10/28
Y1 - 2013/10/28
N2 - 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.
AB - 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.
KW - Astrocyte activation
KW - Cytokines
KW - Iron
KW - Microglia
KW - Nrf2
KW - Oxidative stress
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U2 - 10.1186/1742-2094-10-130
DO - 10.1186/1742-2094-10-130
M3 - Article
VL - 10
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
SN - 1742-2094
M1 - 130
ER -