PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation

Min Xie,Ling Zeng,Lizhi Cao,Minghua Yang,Jianxin Jiang,Xiaofang Sun,Timothy R Billiar,Rui Kang,Yan Yu,Daolin Tang,Shan Zhu,Haichao Wang,Liangchun Yang

doi:10.1038/ncomms13280

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.

Highlights

Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units
Shikonin did not affect the release of IL-1b, IL-18 and high mobility group box 1 (HMGB1) that was induced by NLR family, pyrin domain containing 1 (NLRP1) inflammasome activators (for example, muramyl dipeptide (MDP)) or NLR family, CARD domain containing 4 (NLRC4) inflammasome activators (Fig. 1a)
Given the important role of caspase-1 in canonical inflammasome-mediated secretion of proinflammatory cytokines, we examined the effect of PKM2 inhibition on caspase-1 activation using a fluorometric activity assay kit that recognizes the sequence YVAD

Summary

Introduction

Severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. 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. Pharmacological and genetic inhibition of the PKM2–EIF2AK2 pathway attenuates activation of NLRP3 and AIM2 inflammasomes and limits the release of IL-1b, IL-18 and HMGB1 in vitro or in vivo. These findings improve our understanding of the emerging role of immunometabolism in inflammation and will guide future development of therapeutic strategies to treat sepsis

Methods

Results

Conclusion