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  • Although AMPK is a negative regulator of bioenergetic reprog

    2024-02-22

    Although AMPK is a negative regulator of bioenergetic reprogramming in cancer cells, little is known about the role of AMPK in immunometabolism in sepsis. Our current study indicates that AMPKα dysfunction enhances PKM2-dependent aerobic glycolysis, which results in HMGB1 release in macrophages and monocytes. Hypoxia inducible factor 1α (HIF1α) plays a key role in the metabolic reprogramming by activating transcription of glycolysis-associated genes, including PKM2 (Corcoran and O'Neill, 2016). Interestingly, AMPK inhibits HIF1α transcriptional activity in cancer sitagliptin phosphate (Faubert et al., 2013); suggesting that AMPK possibly plays a role in the downregulation of PKM2 expression through blocking HIF1α activity. Importantly, inhibiting PKM2 reverses the metabolic effects of AMPKα loss on HMGB1 release. Our previous studies showed that the PKM2 pathway contributes to HMGB1 release in at least two ways. As the end product of PKM2-dependent aerobic glycolysis, accumulated lactate can inhibit the activity of histone deacetylases, which is critical in regulating acetylated HMGB1 release (Yang et al., 2014). In addition, PKM2-mediated lactate production promotes HMGB1 release by macrophages through selective activation of inflammasome, a multimolecular complex that senses pathogens and endogenous danger signals and stimulates an inflammatory response (Xie et al., 2016). However, the direct link between HMGB1 acetylation and inflammasome activation remains to be further documented. PKM2 catalyzes the final and also a rate-limiting reaction in the glycolytic pathway. We demonstrated that suppression of glycolysis via PKM2 inhibition can restore mitochondrial respiration in macrophages and monocytes. The mammalian mitochondrial electron transport chain (ETC) consists of five enzyme complexes (complexes I-V) to produce ATP. A recent study showed that the expression level of ETC complexes I, III, and V was reduced in PKM2-overexpressed cancer cells (Wu et al., 2016). This process, mediated by PKM2, requires activation of mitochondrial fusion through proteasome-dependent p53 degradation (Wu et al., 2016), indicating a link between PKM2 expression, mitochondrial defection, and protein degradation. Indirect AMPK activators, including metformin (Tsoyi et al., 2011, Liang et al., 2016), quercetin (Tang et al., 2009, Wang et al., 2014), and resveratrol (Xu et al., 2014), have been proven to protect against experimental sepsis partly through inhibition of HMGB1 release in vivo; however, the impact of direct AMPK activator in HMGB1 release in vivo remains largely unknown. We found that A-769662, a direct and reversible activator of AMPK, significantly reduced mouse death and circulating HMGB1 levels in endotoxic shock and polymicrobial sepsis. Other mechanisms, such as suppression of TLR4, IL-6, and IL-1β expression and/or release, may contribute to the anti-inflammatory activity of A-769662 in vitro and in vivo (Rameshrad et al., 2016, Wang et al., 2016, Zhao et al., 2014, Salvado et al., 2013). Of note, overexpression of HMGB1 results in the inhibition of AMPK activation in cancer cells, indicating a sitagliptin phosphate feedback loop between HMGB1 and AMPK. A key finding in our study is the contribution of AMPKα deficiency in myeloid cells to the abnormal metabolism and inflammation that supports sepsis development. Compared to control mice, AMPKα−/− mice were sensitive to endotoxic shock and polymicrobial sepsis with increased lactate production and HMGB1 release. Notably, pharmacologic inhibition of PKM2 by shikonin decreased septic death in AMPKα−/− mice by modulating lactate production and ameliorating HMGB1 release. These findings indicate that the PKM2-dependent Warburg effect is a driver of HMGB1 release in sepsis in AMPKα−/− mice. Consistent with this idea, our previous study showed that conditional knockout of PKM2 in myeloid cells prevents sepsis-induced HMGB1 release and lethal inflammation in mice (Xie et al., 2016).