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PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation

Author

Listed:
  • Min Xie

    (Xiangya Hospital, Central South University)

  • Yan Yu

    (Xiangya Hospital, Central South University
    University of Pittsburgh)

  • Rui Kang

    (University of Pittsburgh)

  • Shan Zhu

    (Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University)

  • Liangchun Yang

    (Xiangya Hospital, Central South University)

  • Ling Zeng

    (University of Pittsburgh
    State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People’s Liberation Army, Daping Hospital, Third Military Medical University)

  • Xiaofang Sun

    (Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University)

  • Minghua Yang

    (Xiangya Hospital, Central South University)

  • 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)

  • Jianxin Jiang

    (State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People’s Liberation Army, Daping Hospital, Third Military Medical University)

  • Daolin Tang

    (University of Pittsburgh
    Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University)

Abstract

Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2–EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis.

Suggested Citation

  • Min Xie & Yan Yu & Rui Kang & Shan Zhu & Liangchun Yang & Ling Zeng & Xiaofang Sun & Minghua Yang & Timothy R. Billiar & Haichao Wang & Lizhi Cao & Jianxin Jiang & Daolin Tang, 2016. "PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13280
    DOI: 10.1038/ncomms13280
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    Cited by:

    1. Kaiser Wani & Hind AlHarthi & Amani Alghamdi & Shaun Sabico & Nasser M. Al-Daghri, 2021. "Role of NLRP3 Inflammasome Activation in Obesity-Mediated Metabolic Disorders," IJERPH, MDPI, vol. 18(2), pages 1-21, January.

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