W107 - Interferon-induced Mitochondrial Dysfunction in Myositis: From Mice to Men

Iago Pinal-Fernandez – National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health; Andrew Mammen – National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health; Olivier Boyer – Inserm 1234, FCE PAn'THER

Abstract Text: Myositis are autoimmune and inflammatory disorders leading to skeletal muscle weakness and disability. Human studies suggest a role for type I and II interferons in the pathogenesis of the disease. We have shown that ICOS pathway invalidation in NOD mice results in a switch of autoimmunity from diabetes towards myositis, providing a valuable murine model. Indeed Icos-/- NOD mice exhibit reduced muscle strength and muscle histopathological features including macrophage and IFNg-secreting CD4 T cell infiltration. Spatial transcriptome analysis revealed a strong downregulation of genes encoding proteins involved in key mitochondrial metabolic processes, mitochondrial dynamics and structure stability in myofibers from diseased mice close to inflammatory infiltrates. IFNg-blocking antibodies dramatically reduced mitochondrial abnormalities and haltered myositis clinical progression, indicating a pathogenic role for IFNg as a mediator of mitochondrial dysfunction in myofibers. Bulk transcriptome analysis of muscle biopsies from myositis patients revealed a negative correlation between IFNg and mitochondrial gene expression signatures. In addition, exposure of human myoblasts to IFNg in vitro significantly diminished mitochondrial gene expression. All these data support a link between IFNg and mitochondrial dysfunction and suggest a self-maintenance loop between mitochondrial dysfunction and inflammation, opening perspectives for mitochondria therapy in myositis.