IFNγ causes mitochondrial dysfunction and oxidative stress in myositis

Area of Science:

• Immunology
• Mitochondrial Biology
• Muscle Pathophysiology

Background:

• Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with unknown causes and limited treatment options.
• Previous studies showed that mice lacking inducible T cell co-stimulator (Icos) develop spontaneous interferon gamma (IFNγ)-driven myositis, mimicking human IIMs.

Purpose of the Study:

• To investigate the role of IFNγ in IIM pathogenesis.
• To explore the connection between IFNγ, mitochondrial dysfunction, and oxidative stress in myositis.

Main Methods:

• Proteomic and spatial transcriptomic analyses of muscle tissue from Icos-deficient mice.
• Assessment of mitochondrial structure and function, and oxidative stress markers.
• Treatment with a reactive oxygen species (ROS) buffer and anti-IFNγ antibodies.
• Transcriptomic analysis of IIMs patient samples and in vitro human myoblast studies.

Main Results:

• IFNγ induced significant myofiber metabolic dysregulation, mitochondrial abnormalities, and oxidative stress in Icos-deficient mice.
• ROS buffering alleviated myositis, improved mitochondrial function, and reduced inflammation.
• Anti-IFNγ treatment diminished mitochondrial anomalies and oxidative stress.
• Human IIMs data corroborated the link between IFNγ and mitochondrial dysfunction.

Conclusions:

• IFNγ plays a critical role in driving myositis through mitochondrial dysfunction and oxidative stress.
• A self-sustaining loop exists between mitochondrial dysfunction, ROS production, and inflammation in myositis.
• Targeting mitochondria or ROS presents a promising therapeutic strategy for myositis.