IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis.
Fiche publication
Date publication
juin 2017
Journal
Acta neuropathologica
Auteurs
Membres identifiés du Cancéropôle Est :
Dr METZGER Daniel, Dr LAVERNY Gilles, Pr GOTTENBERG Jacques-Eric, Pr GENY Bernard
Tous les auteurs :
Meyer A, Laverny G, Allenbach Y, Grelet E, Ueberschlag V, Echaniz-Laguna A, Lannes B, Alsaleh G, Charles AL, Singh F, Zoll J, Lonsdorfer E, Maurier F, Boyer O, Gottenberg JE, Nicot AS, Laporte J, Benveniste O, Metzger D, Sibilia J, Geny B
Lien Pubmed
Résumé
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.
Mots clés
Acetylcysteine, pharmacology, Adult, Aged, Animals, Cell Line, Cytokines, blood, Dermatomyositis, drug therapy, Female, Free Radical Scavengers, pharmacology, Freund's Adjuvant, Humans, Inflammation, drug therapy, Interferon-beta, metabolism, Male, Mice, Inbred BALB C, Middle Aged, Mitochondria, drug effects, Muscle Weakness, drug therapy, Muscle, Skeletal, drug effects, Nervous System Autoimmune Disease, Experimental, drug therapy, Reactive Oxygen Species, metabolism, Transcriptome
Référence
Acta Neuropathol.. 2017 Jun;: