Document Type
Article
Publication Date
5-20-2025
Original Citation
VanPortfliet J,
Lei Y,
Ramanathan M,
Martinez C,
Wong J,
Stodola T,
Hoffmann B,
Pflug K,
Sitcheran R,
Kneeland SC,
Murray S,
McGuire P,
Cannon C,
West A.
Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease. Nat Commun. 2025;16(1):4640.
Keywords
JMG, SS1, Animals, DNA Polymerase gamma, Macrophages, Mice, Mitochondrial Diseases, Pseudomonas aeruginosa, Caspases, Initiator, DNA-Directed DNA Polymerase, Disease Models, Animal, Inflammation, Pseudomonas Infections, Mice, Inbred C57BL, Immunity, Innate, Interferon Type I, Humans, Mice, Knockout, Cytokines, Male, Female, Mitochondria
JAX Source
Nat Commun. 2025;16(1):4640.
ISSN
2041-1723
PMID
40393978
DOI
https://doi.org/10.1038/s41467-025-59907-8
Grant
This research was supported by awards W81XWH-17-1-0052 to A.P.W. and W81XWH-20-1-0150 to C.C. and A.P.W. from the Office of the Assistant Secretary of Defense and for Health Affairs through the Peer Reviewed Medical Research Programs. Additional support was provided by NIH grants R01HL148153 to A.P.W., U54OD030187 to S.A.M., and a gift from the POLG Foundation. J.J.V. was supported by NIH NRSA F31AI179168, and Y. Lei was supported by American Heart Association Predoctoral Fellowship grant 825908.
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.