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

被引：106

作者：

Meyer, Alain ^{[1
,2
,3
]}

Laverny, Gilles ^{[3
,4
]}

Allenbach, Yves ^{[5
,6
]}

Grelet, Elise ^{[3
,4
]}

Ueberschlag, Vanessa ^{[3
,4
]}

Echaniz-Laguna, Andoni ^{[7
]}

Lannes, Beatrice ^{[8
]}

Alsaleh, Ghada ^{[3
]}

Charles, Anne Laure ^{[1
,3
]}

Singh, Francois ^{[1
,3
]}

Zoll, Joffrey ^{[1
,3
]}

Lonsdorfer, Evelyne ^{[1
,3
]}

Maurier, Francois ^{[9
]}

Boyer, Olivier ^{[10
]}

Gottenberg, Jacques-Eric ^{[2
,3
]}

Nicot, Anne Sophie ^{[3
,4
]}

Laporte, Jocelyn ^{[3
,4
]}

Benveniste, Olivier ^{[5
,6
]}

Metzger, Daniel ^{[3
,4
]}

Sibilia, Jean ^{[2
,3
]}

Geny, Bernard ^{[1
,3
]}

机构：

[1] Hop Univ Strasbourg, Inst Physiol, Serv Physiol & Explorat Fonct, EA 3072, Strasbourg, France

[2] Hop Univ Strasbourg, Ctr Reference Malad Autoimmunes Rares, Strasbourg, France

[3] Univ Strasbourg, Federat Med Translat Strasbourg, Strasbourg, France

[4] INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, UMR 7104,U964, Illkirch Graffenstaden, France

[5] UPMC Univ Paris 06, Sorbonne Univ,Pitie Salpetriere Univ Hosp,AP HP, I2B,Ctr Reference Malad Neuromusculaires Paris Es, Dept Med Interne,UMR 974,Myol Res Ctr,Inserm,DHU, Paris, France

[6] UPMC Univ Paris 06, Sorbonne Univ,Pitie Salpetriere Univ Hosp,AP HP, Ctr Reference Malad Neuromusculaires Paris Est, Immunol Clin,UMR 974,Myol Res Ctr,Inserm,DHU,I2B, Paris, France

[7] Hop Univ Strasbourg, Serv Neurol, Ctr Reference Malad Neuromusculaires, Strasbourg, France

[8] Univ Strasbourg, Hop Univ Strasbourg, Federat Med Translat, Dept Pathol, Strasbourg, France

[9] Hop Prives Metz, Ctr Competences Malad Syst Rares, Serv Med Interne, Metz, France

[10] Univ Normandie, INSERM, U905, Rouen, France

来源：

ACTA NEUROPATHOLOGICA | 2017年 / 134卷 / 04期

关键词：

SKELETAL-MUSCLE; OXIDATIVE STRESS; PHYSICAL-ACTIVITY; AEROBIC CAPACITY; POLYMYOSITIS; CELLS; DYSFUNCTION; MYOPATHIES; EXERCISE; IMMUNE;

D O I：

10.1007/s00401-017-1731-9

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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-beta 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-beta 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.

引用

页码：655 / 666

页数：12

共 51 条

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