title: PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis.
abstract: 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.
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Liangchun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Surgery, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Surgery, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Surgery, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Department of Surgery, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Surgery, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019446:Endotoxemia / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics / Q000502:physiology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010085:Oxidative Phosphorylation; D018805:Sepsis / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D024243:HMGB1 Protein; D008565:Membrane Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins