Deficiency of Myeloid Pfkfb3 Protects Mice From Lung Edema and Cardiac Dysfunction in LPS-Induced Endotoxemia

• Type of Material: Article
• Authors: Jiean Xu, Peking University; Lina Wang, Augusta University; Qiuhua Yang, Augusta University; Qian Ma, Augusta University; Yaqi Zhou, Augusta University; Yongfeng Cai, Augusta University; Xiaoxiao Mao, Augusta University; Qingen Da, Peking University Shenzhen Hospital; Tammy Lu, Emory University; Yunchao Su, Augusta University; Zsolt Bagi, Augusta University; Rudolf Lucas, Augusta University; Zhiping Liu, Jinan University; Mei Hong, Peking University; Kunfu Ouyang, Peking University; Yuqing Huo, Augusta University
• Language: English
• Date: 2021-09-29
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Xu, Wang, Yang, Ma, Zhou, Cai, Mao, Da, Lu, Su, Bagi, Lucas, Liu, Hong, Ouyang and Huo.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fcvm.2021.745810
• Title of Journal or Parent Work: FRONTIERS IN CARDIOVASCULAR MEDICINE
• Volume: 8
• Start Page: 745810
• End Page: 745810
• Grant/Funding Information: This work was supported in part or in whole by grants from National Science Foundation of China Grants 82100506, 81870324, and 82070461; China Postdoctoral Science Foundation 2020M680003 and 2020M670051; Guangdong Basic and Applied Basic Research Foundation 2020A1515010010 and 2019A1515110111; Shenzhen Science and Technology Innovation Committee Grants JCYJ20190808155605447, JCYJ20170810163238384, JCYJ20190808155801648, JCYJ201704121-50405310, and GXWD20201231165807007-20200818123312001. Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions 2019SHIBS0004; American Heart Association Grant 19TPA34910043. National Institutes of Health Grants R01HL134934, R01EY030500, R01HL142097, and R01HL138410. VA Merit Review Grant BX002035.
• Keywords: KINASE; Cardiac & Cardiovascular Systems; ACTIVATION; GLYCOLYSIS; PFKFB3; macrophage; SEPTIC SHOCK; endotoxemia; Science & Technology; NF-KAPPA-B; PHOSPHORYLATION; Cardiovascular System & Cardiology; SEPSIS; inflammation; CELLS; MACROPHAGE METABOLISM; Life Sciences & Biomedicine; 6-PHOSPHOFRUCTO-2-KINASE; glycolysis
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology

Abstract

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-κB 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.