PMID- 34660743 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231021 IS - 2297-055X (Print) IS - 2297-055X (Electronic) IS - 2297-055X (Linking) VI - 8 DP - 2021 TI - Deficiency of Myeloid Pfkfb3 Protects Mice From Lung Edema and Cardiac Dysfunction in LPS-Induced Endotoxemia. PG - 745810 LID - 10.3389/fcvm.2021.745810 [doi] LID - 745810 AB - Sepsis, a pathology resulting from excessive inflammatory response that leads to multiple organ failure, is a major cause of mortality in intensive care units. Macrophages play an important role in the pathophysiology of sepsis. Accumulating evidence has suggested an upregulated rate of aerobic glycolysis as a key common feature of activated proinflammatory macrophages. Here, we identified a crucial role of myeloid 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3), a glycolytic activator in lipopolysaccharide (LPS)-induced endotoxemia in mice. Pfkfb3 expression is substantially increased in bone marrow derived macrophages (BMDMs) treated with LPS in vitro and in lung macrophages of mice challenged with LPS in vivo. Myeloid-specific knockout of Pfkfb3 in mice protects against LPS-induced lung edema, cardiac dysfunction and hypotension, which were associated with decreased expression of interleukin 1 beta (Il1b), interleukin 6 (Il6) and nitric oxide synthase 2 (Nos2), as well as reduced infiltration of neutrophils and macrophages in lung tissue. Pfkfb3 ablation in cultured macrophages attenuated LPS-induced glycolytic flux, resulting in a decrease in proinflammatory gene expression. Mechanistically, Pfkfb3 ablation or inhibition with a Pfkfb3 inhibitor AZ26 suppresses LPS-induced proinflammatory gene expression via the NF-kappaB signaling pathway. In summary, our study reveals the critical role of Pfkfb3 in LPS-induced sepsis via reprogramming macrophage metabolism and regulating proinflammatory gene expression. Therefore, PFKFB3 is a potential target for the prevention and treatment of inflammatory diseases such as sepsis. CI - Copyright (c) 2021 Xu, Wang, Yang, Ma, Zhou, Cai, Mao, Da, Lu, Su, Bagi, Lucas, Liu, Hong, Ouyang and Huo. FAU - Xu, Jiean AU - Xu J AD - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China. AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Wang, Lina AU - Wang L AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Yang, Qiuhua AU - Yang Q AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Ma, Qian AU - Ma Q AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Zhou, Yaqi AU - Zhou Y AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Cai, Yongfeng AU - Cai Y AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Mao, Xiaoxiao AU - Mao X AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Da, Qingen AU - Da Q AD - Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen, China. FAU - Lu, Tammy AU - Lu T AD - Oxford College, Emory University, Oxford, GA, United States. FAU - Su, Yunchao AU - Su Y AD - Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Bagi, Zsolt AU - Bagi Z AD - Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Lucas, Rudolf AU - Lucas R AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. FAU - Liu, Zhiping AU - Liu Z AD - College of Pharmacy, Jinan University, Guangzhou, China. FAU - Hong, Mei AU - Hong M AD - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China. FAU - Ouyang, Kunfu AU - Ouyang K AD - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China. AD - Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen, China. FAU - Huo, Yuqing AU - Huo Y AD - Department of Cellular Biology and Anatomy, Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States. LA - eng GR - R01 HL138410/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20210929 PL - Switzerland TA - Front Cardiovasc Med JT - Frontiers in cardiovascular medicine JID - 101653388 PMC - PMC8511447 OTO - NOTNLM OT - PFKFB3 OT - endotoxemia OT - glycolysis OT - inflammation OT - macrophage COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/10/19 06:00 MHDA- 2021/10/19 06:01 PMCR- 2021/01/01 CRDT- 2021/10/18 09:09 PHST- 2021/07/22 00:00 [received] PHST- 2021/09/06 00:00 [accepted] PHST- 2021/10/18 09:09 [entrez] PHST- 2021/10/19 06:00 [pubmed] PHST- 2021/10/19 06:01 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fcvm.2021.745810 [doi] PST - epublish SO - Front Cardiovasc Med. 2021 Sep 29;8:745810. doi: 10.3389/fcvm.2021.745810. eCollection 2021.