title: PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation.
abstract: 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.
authors: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Min
authors: M
authors: Xie
authors: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors: Yan
authors: Y
authors: Yu
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors: Rui
authors: R
authors: Kang
authors: Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors: Shan
authors: S
authors: Zhu
authors: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Liangchun
authors: L
authors: Yang
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.|State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors: Ling
authors: L
authors: Zeng
authors: Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors: Xiaofang
authors: X
authors: Sun
authors: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Minghua
authors: M
authors: Yang
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors: Timothy R
authors: TR
authors: Billiar
authors: Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors: Haichao
authors: 0000-0002-0211-9000
authors: H
authors: Wang
authors: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Lizhi
authors: L
authors: Cao
authors: State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors: Jianxin
authors: J
authors: Jiang
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.|Center of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors: Daolin
authors: D
authors: Tang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D060085:Coinfection / Q000276:immunology* / Q000382:microbiology; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006019:Glycolysis / Q000276:immunology*; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D010766:Phosphorylation; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology; D015398:Signal Transduction / Q000276:immunology; D013963:Thyroid Hormones / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D024243:HMGB1 Protein; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008565:Membrane Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009285:Naphthoquinones; D011770:Pyruvate Kinase; D013963:Thyroid Hormones; D019892:eIF-2 Kinase; D000097810:Thyroid Hormone-Binding Proteins; C540422:Aim2 protein, mouse; C582808:HMGB1 protein, mouse; C587672:IL1B protein, mouse; C492716:Nlrp3 protein, mouse; C016101:shikonin; C000628218:Pkm protein, mouse; C000605978:protein kinase R, mouse