The proinflammatory action of microglial P2 receptors is enhanced in SOD1 models for amyotrophic lateral sclerosis

Nadia D'Ambrosi, Pamela Finocchi, Savina Apolloni, Mauro Cozzolino, Alberto Ferri, Valeria Padovano, Grazia Pietrini, Maria Teresa Carri, Cinzia Volonte

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of lower and upper motoneurons. The pathology is imputable in ∼2% of cases to mutations in the ubiquitous enzyme Cu, Zn superoxide dismutase (SOD1). Common theories to explain the pathogenic mechanisms of ALS include activation of microglia, responsible for the release of proinflammatory factors. However, how mutant SOD1 affects microglial activation and subsequently injures neurons is still unclear. Considering that extracellular ATP, through purinergic P2 receptors, constitutes a well recognized neuron-to-microglia alarm signal, the aim of this study was to investigate how the expression of mutant SOD1 affects P2 receptor-mediated proinflammatory microglial properties. We used primary and immortalized microglial cells from mutant SOD1 mice to explore several aspects of activation by purinergic ligands and to analyze the overall effect of such stimulation on the viability of NSC-34 and SH-SY5Y neuronal cell lines. We observed up-regulation of P2X4, P2X7, and P2Y6 receptors and down-regulation of ATP-hydrolyzing activities in mutant SOD1 microglia. This potentiation of the purinergic machinery reflected into enhanced sensitivity mainly to 2′-3′-O-(benzoyl-benzoyl) ATP, a P2X 7 receptor preferential agonist, and translated into deeper morphological changes, enhancement of TNF-α and cyclooxygenase-2 content, and finally into toxic effects exerted on neuronal cell lines by microglia expressing mutant SOD1. All these parameters were prevented by the antagonist Brilliant Blue G. The purinergic activation of microglia may thus constitute a new route involved in the progression of ALS to be exploited to potentially halt the disease.

Original languageEnglish
Pages (from-to)4648-4656
Number of pages9
JournalJournal of Immunology
Volume183
Issue number7
DOIs
Publication statusPublished - Oct 1 2009

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ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

D'Ambrosi, N., Finocchi, P., Apolloni, S., Cozzolino, M., Ferri, A., Padovano, V., Pietrini, G., Carri, M. T., & Volonte, C. (2009). The proinflammatory action of microglial P2 receptors is enhanced in SOD1 models for amyotrophic lateral sclerosis. Journal of Immunology, 183(7), 4648-4656. https://doi.org/10.4049/jimmunol.0901212