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Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease
Jordyn J VanPortfliet1,2, Yuanjiu Lei2,3, Muthumeena Ramanathan1
1The Jackson Laboratory, Bar Harbor, ME, USA.
Abstract:
Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.
Insights
Mitochondrial diseases (MtD) involve immune system overactivity, particularly in the lungs. This study identifies specific immune pathways that worsen lung inflammation and illness in mouse models of polymerase gamma (Polg)-related MtD.
Area of Science:
- Immunology
- Mitochondrial Biology
- Infectious Disease
Background:
- Mitochondrial diseases (MtD) present diverse, severe symptoms and lack effective treatments.
- Environmental factors like infections can worsen MtD by impairing mitochondrial function.
- The immune system's role in MtD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the molecular and cellular mechanisms behind innate immune hyperactivity in polymerase gamma (Polg)-related MtD.
- To clarify how immune alterations contribute to immunopathology in MtD.
- To identify potential therapeutic targets for infection-related complications in MtD.
Main Methods:
- In vitro and in vivo experimental approaches.
- Utilized mouse models of Polg-related MtD.
- Analyzed immune responses to Pseudomonas aeruginosa infection.
Main Results:
- Type I interferon (IFN-I) signaling upregulates caspase-11 and guanylate-binding proteins (GBP) in Polg mutant mice.
- Enhanced immune cell sensing of Pseudomonas aeruginosa (PA) was observed.
- Excessive cytokine release and pyroptotic cell death pathways exacerbated lung inflammation and morbidity.
Conclusions:
- Established a mechanistic framework for innate immune dysregulation in MtD.
- Highlighted the role of IFN-I, caspase-11, and GBP in exacerbating PA infection in Polg-related MtD.
- Identified potential therapeutic targets for managing infection and inflammation in MtD.
