PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation.
Min XieYan YuRui KangShan ZhuLiangchun YangLing ZengXiaofang SunMinghua YangTimothy R BilliarHaichao WangLizhi CaoJianxin JiangDaolin TangPublished in: Nature communications (2016)
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.
Keyphrases
- septic shock
- intensive care unit
- acute kidney injury
- inflammatory response
- signaling pathway
- induced apoptosis
- cardiovascular events
- acute myeloid leukemia
- gene expression
- dendritic cells
- adipose tissue
- cardiovascular disease
- left ventricular
- early onset
- extracorporeal membrane oxygenation
- metabolic syndrome
- skeletal muscle
- toll like receptor
- current status
- mechanical ventilation
- cell death