PKM2-Dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation

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

Research output: Contribution to journalArticle

108 Scopus citations

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.

Original languageEnglish (US)
Article number13280
JournalNature communications
Volume7
DOIs
StatePublished - Oct 25 2016
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Xie, M., Yu, Y., Kang, R., Zhu, S., Yang, L., Zeng, L., Sun, X., Yang, M., Billiar, T. R., Wang, H., Cao, L., Jiang, J., & Tang, D. (2016). PKM2-Dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. Nature communications, 7, [13280]. https://doi.org/10.1038/ncomms13280