IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis

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ID: 111023
2017
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Abstract
Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-β induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-β induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.
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meyer2017actaifn-β-induced Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Alain Meyer;Gilles Laverny;Yves Allenbach;Elise Grelet;Vanessa Ueberschlag;Andoni Echaniz-Laguna;Béatrice Lannes;Ghada Alsaleh;Anne Laure Charles;François Singh;Joffrey Zoll;Evelyne Lonsdorfer;François Maurier;Olivier Boyer;Jacques-Eric Gottenberg;Anne Sophie Nicot;Jocelyn Laporte;Olivier Benveniste;Daniel Metzger;Jean Sibilia;Bernard Geny;Alain Meyer;Gilles Laverny;Yves Allenbach;Elise Grelet;Vanessa Ueberschlag;Andoni Echaniz-Laguna;Béatrice Lannes;Ghada Alsaleh;Anne Laure Charles;François Singh;Joffrey Zoll;Evelyne Lonsdorfer;François Maurier;Olivier Boyer;Jacques-Eric Gottenberg;Anne Sophie Nicot;Jocelyn Laporte;Olivier Benveniste;Daniel Metzger;Jean Sibilia;Bernard Geny;
Journal acta neuropathologica
Year 2017
DOI
doi:10.1007/s00401-017-1731-9
URL
https://link.springer.com/article/10.1007/s00401-017-1731-9
Keywords
pathology neurosciences

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