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PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis

Author

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  • Liangchun Yang

    (Xiangya Hospital, Central South University)

  • Min Xie

    (Xiangya Hospital, Central South University)

  • Minghua Yang

    (Xiangya Hospital, Central South University)

  • Yan Yu

    (Xiangya Hospital, Central South University)

  • Shan Zhu

    (Xiangya Hospital, Central South University)

  • Wen Hou

    (University of Pittsburgh)

  • Rui Kang

    (University of Pittsburgh)

  • Michael T. Lotze

    (University of Pittsburgh)

  • Timothy R. Billiar

    (University of Pittsburgh)

  • Haichao Wang

    (Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research)

  • Lizhi Cao

    (Xiangya Hospital, Central South University)

  • Daolin Tang

    (University of Pittsburgh)

Abstract

Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high-mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1α (HIF1α) and activates the HIF-1α-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1α and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels, and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases.

Suggested Citation

  • Liangchun Yang & Min Xie & Minghua Yang & Yan Yu & Shan Zhu & Wen Hou & Rui Kang & Michael T. Lotze & Timothy R. Billiar & Haichao Wang & Lizhi Cao & Daolin Tang, 2014. "PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5436
    DOI: 10.1038/ncomms5436
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    Cited by:

    1. Meiyue Wang & Heinrich Flaswinkel & Abhinav Joshi & Matteo Napoli & Sergi Masgrau-Alsina & Julia M. Kamper & Antonia Henne & Alexander Heinz & Marleen Berouti & Niklas A. Schmacke & Karsten Hiller & E, 2024. "Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Veli Bakalov & Laura Reyes-Uribe & Rahul Deshpande & Abigail L Maloy & Steven D Shapiro & Derek C Angus & Chung-Chou H Chang & Laurence Le Moyec & Stacy Gelhaus Wendell & Ata Murat Kaynar, 2020. "Dichloroacetate-induced metabolic reprogramming improves lifespan in a Drosophila model of surviving sepsis," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-18, November.

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