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Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages

Cellular & Molecular Immunology volume 20, pages 131–142 (2023)Cite this article

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Abstract

Polyribonucleotide nucleotidyltransferase 1 (Pnpt1) plays critical roles in mitochondrial homeostasis by controlling mitochondrial RNA (mt-RNA) processing, trafficking and degradation. Pnpt1 deficiency results in mitochondrial dysfunction that triggers a type I interferon response, suggesting a role in inflammation. However, the role of Pnpt1 in inflammasome activation remains largely unknown. In this study, we generated myeloid-specific Pnpt1-knockout mice and demonstrated that Pnpt1 depletion enhanced interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion in a mouse sepsis model. Using cultured peritoneal and bone marrow-derived macrophages, we demonstrated that Pnpt1 regulated NLRP3 inflammasome-dependent IL-1β release in response to lipopolysaccharide (LPS), followed by nigericin, ATP or poly (I:C) treatment. Pnpt1 deficiency in macrophages increased glycolysis after LPS administration and mt-reactive oxygen species (mt-ROS) after NLRP3 inflammasome activation. Pnpt1 activation of the inflammasome was dependent on increased glycolysis and the expression of mitochondrial antiviral-signaling protein (MAVS) but not NF-κB signaling. Collectively, these data suggest that Pnpt1 is an important mediator of inflammation, as shown by activation of the NLRP3 inflammasome in murine sepsis and cultured macrophages.

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Data availability

All data generated or analyzed during this study are included in this published paper and in its supplementary file.

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Acknowledgements

We thank Amanda Pereira and Sharon Senchanthisai for assistance with the maintenance and breeding of mice.

Funding

This work was financially supported by the National Institute of Health (HL140958 to BCB), the Department of Defense (DM190884 to BCB), New York State Department of Health (C34726GG to BCB and CGH), University of Rochester Environmental Health Sciences Center (P30 ES001247 to BCB), and the National Natural Science Foundation of China (No. 82200268 to WJL).

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Author notes

  1. These authors contributed equally: Chia George Hsu, Wenjia Li.

Authors and Affiliations

  1. Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA

    Chia George Hsu, Wenjia Li, Mark Sowden, Camila Lage Chávez & Bradford C. Berk

  2. Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China

    Wenjia Li

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  1. Chia George Hsu
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Contributions

CGH, WJL, MS, and BCB designed the research. CGH, WJL, CLC, and MS performed the research. BCB contributed new reagents/analytical tools. CGH and WJL analyzed the data. CGH, WJL, and BCB wrote the paper.

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Correspondence to Bradford C. Berk.

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The authors declare no competing interests.

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All of the experiments were approved by the University Committee on Animal Use for Research (UCAR) at the University of Rochester and followed the National Institutes of Health guidelines for experimental procedures on mice.

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Hsu, C.G., Li, W., Sowden, M. et al. Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages. Cell Mol Immunol 20, 131–142 (2023). https://doi.org/10.1038/s41423-022-00962-2

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Keywords

  • Pnpt1
  • Inflammasome
  • Mitochondria
  • Macrophage

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