Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease
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.
Authors
- Kathryn M. Pflug (ORCID: https://orcid.org/0000-0002-2472-0876)
- Murali Krishna Ramanathan (ORCID: https://orcid.org/0000-0002-9943-150X)
- Timothy J. Stodola (ORCID: https://orcid.org/0000-0001-9671-884X)
- Camila Guerra Martinez (ORCID: https://orcid.org/0000-0001-6116-9182)
- Stephen A. Murray (ORCID: https://orcid.org/0000-0002-0594-1702)
- Peter J. McGuire (ORCID: https://orcid.org/0000-0001-5601-3044)
- Jordyn J. VanPortfliet (ORCID: https://orcid.org/0000-0002-2210-4914)
- Carolyn L. Cannon (ORCID: https://orcid.org/0000-0002-2491-0389)
- Jessica K. Wong (ORCID: https://orcid.org/0000-0003-1709-3357)
- Stephen C. Kneeland
- A. Phillip West (ORCID: https://orcid.org/0000-0003-2884-6895)
- Brian Hoffmann (ORCID: https://orcid.org/0000-0002-7526-6335)
- Yuanjiu Lei (ORCID: https://orcid.org/0000-0002-7486-4261)
- Raquel Sitcheran (ORCID: https://orcid.org/0000-0001-8916-9707)
Institutions
- National Institutes of Health (US)
- Yale University (US)
- National Human Genome Research Institute (US)
- Texas A&M Health Science Center (US)
- Jackson Laboratory (US)
- Texas A&M University (US)
- Bryan College (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s41467-025-59907-8
- Citations
- 7
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- Congressionally Directed Medical Research Programs