Iron-sulfur glutaredoxin 2 protects oligodendrocytes against damage induced by nitric oxide release from activated microglia

Klaudia Lepka, Katrin Volbracht, Eckhard Bill, Reiner Schneider, Natalia Rios, Thomas Hildebrandt, Jens Ingwersen, Timur Prozorovski, Christopher Horst Lillig, Jack van Horssen, Lawrence Steinman, Hans Peter Hartung, Rafael Radi, Arne Holmgren, Orhan Aktas*, Carsten Berndt

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Demyelinated brain lesions, a hallmark of autoimmune neuroinflammatory diseases like multiple sclerosis, result from oligodendroglial cell damage. Activated microglia are considered a major source of nitric oxide and subsequent peroxynitrite-mediated damage of myelin. Here, we provide biochemical and biophysical evidence that the oxidoreductase glutaredoxin 2 inhibits peroxynitrite formation by transforming nitric oxide into dinitrosyl-diglutathionyl-iron-complexes. Glutaredoxin 2 levels influence both survival rates of primary oligodendrocyte progenitor cells and preservation of myelin structure in cerebellar organotypic slice cultures challenged with activated microglia or nitric oxide donors. Of note, glutaredoxin 2-mediated protection is not linked to its enzymatic activity as oxidoreductase, but to the disassembly of its uniquely coordinated iron-sulfur cluster using glutathione as non-protein ligand. The protective effect of glutaredoxin 2 is connected to decreased protein carbonylation and nitration. In line, brain lesions of mice suffering from experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, show decreased glutaredoxin 2 expression and increased nitrotyrosine formation indicating that this type of protection is missing in the inflamed central nervous system. Our findings link inorganic biochemistry to neuroinflammation and identify glutaredoxin 2 as a protective factor against neuroinflammation-mediated myelin damage. Thus, improved availability of glutathione-coordinated iron-sulfur clusters emerges as a potential therapeutic approach in inflammatory demyelination.

Original languageEnglish
Pages (from-to)1521-1534
Number of pages14
JournalGLIA
Volume65
Issue number9
DOIs
Publication statusPublished - 1 Sep 2017

Cite this

Lepka, K., Volbracht, K., Bill, E., Schneider, R., Rios, N., Hildebrandt, T., ... Berndt, C. (2017). Iron-sulfur glutaredoxin 2 protects oligodendrocytes against damage induced by nitric oxide release from activated microglia. GLIA, 65(9), 1521-1534. https://doi.org/10.1002/glia.23178