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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Bibliographic Details
Published in:Nature communications Vol. 15; no. 1; pp. 5403 - 18
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 26.06.2024
Nature Publishing Group
Nature Portfolio
Subjects:
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14/1
14/105
14/28
14/63
38/77
49/88
631/250/249/1313
631/250/256/2515
631/250/38
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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
Online Access:Get full text
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Summary: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).
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PMCID: PMC11208592
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-49460-1