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

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.

17-(Allylamino)-17demethoxygeldanamycin reduces Endoplasmic Reticulum (ER) stress-induced mitochondrial dysfunction in C2C12 myotubes

“…We therefore suggest that ER stress induces P-JNK/ROS-mediated uncoupling of the ETC, causing decreased oxygen utilisation and ATP synthesis, effects clearly ameliorated by 17AAG. Our narrative of ROS involvement in these processes is supported by recent findings in a murine model of myositis, whereby weakness is associated with interferon-γ-induced ROS generation, [34].…”

N-acetylcysteine versus progesterone on the cisplatin-induced peripheral neurotoxicity

“…Concerning the second studied mechanism of the CIPN, the structure of the mitochondria in the axoplasm was well preserved in the use of both NAC and progesterone. The ability of the NAC and progesterone to restore and preserve the normal mitochondrial function was proved in many studies [3,37,42]. The normal mitochondrial function is important as the mitochondrial dysfunction is the main cause of redox imbalance and apoptosis in peripheral neurons [21].…”

Exacerbation of Murine Experimental Autoimmune Myositis by Toll‐Like Receptor 7/8

“…Viral infection has been convincingly associated with autoimmunity, activation of TLRs, and the generation of potent adjuvant signals such as type I IFNs (15,22,(24)(25)(26)(27)41). Immune complexes containing relevant myositis antigens, including HisRS, stimulate TLRs of IFN-producing cells (42), which are found in the muscle and skin of IIM patients (43) and amplify IFN production in an autocrine manner (44).…”