IFNγ causes mitochondrial dysfunction and oxidative stress in myositis

Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator ( Icos ), which have previously been shown to d...

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Vydáno v:	Nature communications Ročník 15; číslo 1; s. 5403 - 18
Hlavní autoři:	Abad, Catalina, Pinal-Fernandez, Iago, Guillou, Clement, Bourdenet, Gwladys, Drouot, Laurent, Cosette, Pascal, Giannini, Margherita, Debrut, Lea, Jean, Laetitia, Bernard, Sophie, Genty, Damien, Zoubairi, Rachid, Remy-Jouet, Isabelle, Geny, Bernard, Boitard, Christian, Mammen, Andrew, Meyer, Alain, Boyer, Olivier
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 26.06.2024 Nature Publishing Group Nature Portfolio
Témata:	13 13/51 14/1 14/105 14/28 14/63 38/77 49/88 631/250/249/1313 631/250/256/2515 631/250/38 64/60 82/79 Abnormalities Acetylcysteine Adaptive immunology Animals Autoimmune diseases Biochemistry, Molecular Biology Disease Models, Animal Drug delivery Female Genomics Health services Human health and pathology Humanities and Social Sciences Humans Immunology Innate immunity Interferon-gamma - metabolism Life Sciences Lymphocytes Lymphocytes T Metabolism Mice Mice, Inbred NOD Mice, Knockout Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondria, Muscle - metabolism Mitochondria, Muscle - pathology multidisciplinary Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Muscles Myoblasts Myoblasts - metabolism Myositis Myositis - genetics Myositis - metabolism Myositis - pathology Oxidative Stress Pathogenesis Proteomics Reactive oxygen species Reactive Oxygen Species - metabolism Science Science (multidisciplinary) Spatial analysis Stimulators Transcriptomics Ultrastructure γ-Interferon
ISSN:	2041-1723, 2041-1723
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Shrnutí:	Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator ( Icos ), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis. Idiopathic inflammatory myopathies are severe autoimmune diseases with poorly understood pathogenesis. In this study, the authors use Icos-deficient NOD mice as a model for myositis, as well as clinical samples, to demonstrate mitochondrial abnormalities and metabolic dysfunction, which can be reversed by treatment with the ROS scavenger, N-acetylcysteine (NAC).
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC11208592
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-49460-1