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Spatial transcriptome analysis of muscle sections from Icos-/- NOD mice with established myositis

ABSTRACT: Icos-/- NOD mice are a model of spontaneous myositis. By using Nanostring GeoMx technology (Mouse WTA), we aimed to investigate the differences in gene expression between myofibers of Icos+/+ NOD (WT) mice and myofibers from Icos-/- NOD mice either in direct contact or not with large infiltrate clusters.

ORGANISM(S): Mus musculus

PROVIDER: GSE262352 | GEO | 2024/05/29

REPOSITORIES: GEO

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Project description:Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases whose pathogenetic mechanisms are still poorly understood. Invalidation of the inducible T cell co-stimulator (Icos) gene on the diabetes-prone NOD mouse background leads to spontaneous autoimmune myositis, providing a tool for studying the pathophysiological mechanisms involved in muscle inflammation. Myositis in Icos-/- NOD mice is characterized by progressive muscle weakness with immune cell infiltration and expression of IFN-associated genes, thus resembling human myositis. Proteomic and spatial transcriptomic analysis of Icos-/- NOD mice muscle brought to light a profound metabolic dysregulation in myofibers. Electron microscopy analysis, mitochondrial respiration assessment and histoenzymology stainings revealed dramatic structural abnormalities and severe dysfunction of muscle mitochondria in diseased Icos-/- NOD mice. Consequently, muscle from these mice exhibited elevated reactive oxygen species (ROS) production and an oxidative stress-transcriptomic signature. Blocking IFN in Icos-/- NOD mice diminished immune cell infiltration and ROS production. Transcriptomic analysis of muscle biopsies from IIMs patients revealed a negative correlation between IFN and mitochondrial gene expression levels, and treatment of human myoblasts with IFN reduced the expression of mitochondrial respiratory chain genes, suggesting a link between IFN production and mitochondrial dysfunction. Sustaining a relevant pathogenic role for oxidative stress in the disease, preventive and therapeutic ROS-buffer treatments also significantly alleviated myositis while preserving mitochondrial ultrastructure and restoring muscle mitochondrial respiration in mice. Notably, preventive ROS-buffer treatment also reduced muscle inflammation. Together, our results suggest that ROS, mitochondrial dysfunction and inflammation are interconnected in a self-maintenance loop, opening perspectives for ROS targeting drugs and/or mitochondria therapy in myositis.

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Spatial transcriptome analysis of muscle sections from Icos-/- NOD mice with established myositis

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