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

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外文摘要：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.

外文关键词：

Pnpt1InflammasomeMitochondriaMacrophage

作者：

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

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作者单位：

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

基金：

National Institute of HealthDepartment of DefenseNew York State Department of HealthUniversity of Rochester Environmental Health Sciences CenterNational Natural Science Foundation of China

项目编号：

HL140958 to BCBDM190884C34726GGP30 ES00124782200268

出版年：

2023

DOI：

10.1038/s41423-022-00962-2

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(2)

参考文献量56