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Title:
PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis | Nature Communications
Description:
Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high-mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1α (HIF1α) and activates the HIF-1α-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1α and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels, and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases. The role of metabolic reprogramming in the regulation of innate inflammatory response remains incompletely understood. Here, the authors show that pyruvate kinase M2-mediated aerobic glycolysis contributes to inflammatory response, and that inhibition of this pathway protects mice from lethal endotoxemia and sepsis.
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nature portfolio permissions reprints pkm2/stat1-mediated pd-l1 upregulation privacy policy cardiovascular translational research advertising author information authors medical research anti-hmgb1-neutralizing antibody nature 330 nature 418 nature 493 nature 496 nature 452 nature attenuate lps-induced il-1β full access kits japan development gel-pro analyzer software vesicle-mediated secretory pathway ifn-γ-induced hmgb1 release secretory lysosome-mediated exocytosis hypoxia-inducible factor 1α research real-time quantitative pcr metabolism-driven reprogramming dictates hypoxia inducible factor-1alpha enzyme-linked immunosorbant assay rate-limiting reaction step tumour necrosis factor-alpha autocrine hmgb1-dependent pathway peroxidase-conjugated secondary antibodies hypoxia regulates beta-enolase fulfill anti-inflammatory functions full size image tumour necrosis factor-α hif-1α-dependent transcription lps-induced glycolytic genes extracellular signal-regulated kinase targeting hypoxia-induced inflammation lps-induced hmgb1 acetylation pkm2-mediated hif1α activation gram-negative bacterial infection2 pro-inflammatory th17 cells33 bone marrow-derived macrophages growing evidence suggests aerobic glycolysis-related genes lps-induced lactate production
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- A role for the NLRP3 inflammasome in metabolic diseases--did Warburg miss inflammation?
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