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T cell-Macrophage Interactions Mediate Innate and Adaptive Immune Responses in Histidyl-tRNA Synthetase-Induced Myositis

ABSTRACT: The relative contribution of innate and adaptive immunity to idiopathic inflammatory myopathy is poorly defined. We therefore sought to clarify these components of disease pathogenesis using our novel murine model of histidyl-tRNA synthetase (HRS)-induced myositis. Myositis was induced in WT and various congenic strains of C57BL/6 mice through intramuscular immunization with recombinant HRS. Histopathological, immunohistochemical, flow cytometric, and transcriptomic assessments were used to characterize muscle-infiltrating cell populations in these congenic strains. RAG1 KO mice developed markedly reduced muscle inflammation relative to WT mice, demonstrating a key requirement for T cells in driving HRS-induced myositis. Diminished cellular infiltration in CD4-Cre.MyD88fl/fl conditional knockout and OT-II TCR transgenic mice highlighted roles for innate and TCR-mediated/adaptive immune signaling in T cells. Transcriptionally-based pathway analyses showed that disruption of T cell signaling alters the function of macrophages, fibroblasts, and other non-lymphoid cell populations. Overall, these findings demonstrate that HRS-induced myositis reflects complex cellular interactions requiring the activation of both innate and adaptive T cell-mediated signaling pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE229059 | GEO | 2023/10/18

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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T cell-Macrophage Interactions Mediate Innate and Adaptive Immune Responses in Histidyl-tRNA Synthetase-Induced Myositis

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