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

Autor: Hsu CG; Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA., Li W; Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA.; Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China., Sowden M; Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA., Chávez CL; Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA., Berk BC; Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA. Bradford_Berk@urmc.rochester.edu.
Jazyk: angličtina
Zdroj: Cellular & molecular immunology [Cell Mol Immunol] 2023 Feb; Vol. 20 (2), pp. 131-142. Date of Electronic Publication: 2023 Jan 04.
DOI: 10.1038/s41423-022-00962-2
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to CSI and USTC.)
Databáze: MEDLINE
Externí odkaz: