Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms5436
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Funding
- National Natural Sciences Foundation of China [31171328, 81370648, 81270616, 81100359]
- National Institutes of Health [R01CA160417]
- National Center of Complementary and Alternative Medicine [R01AT005076]
- National Institute of General Medical Sciences [R01GM063075, R01GM050441, P50GM053789]
- University of Pittsburgh Cancer Institute [P30CA047904]
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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 1 alpha (HIF1 alpha) and activates the HIF-1 alpha-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1 alpha 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.
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