Methylglyoxal-induced macrophage metabolic dysregulation in sepsis

脓毒症中甲基乙二醛诱导的巨噬细胞代谢失调

• 批准号: 10603677
• 负责人: Daniel Joseph Prantner
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603677
• 关键词: Acute; Aerobic; Aldehyde Reductase; Automobile Driving; Bacteremia; Biological Markers; Cell Respiration; Cells; Cessation of life; Chronic; Complex; Data; Disease; Drug Metabolic Detoxication; Electron Transport Complex III; Enzymes; Exhibits; Fatality rate; Genes; Glycolysis; Goals; Hyperglycemia; Hypoxia; Immune response; Impairment; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Type II; Interferons; Invaded; Isomerase; Lactoylglutathione Lyase; Leukocytes; Lipids; Lipopolysaccharides; Lung; Macrophage; Mediating; Mediator; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Oxidative Phosphorylation; Oxygen; Patients; Peptide Hydrolases; Phase; Phenotype; Production; Proteins; Pyruvaldehyde; Reaction; Reactive Oxygen Species; Reporting; Role; Secondary to; Sepsis; Septic Shock; Serum; Severity of illness; Signal Pathway; Signal Transduction Pathway; Stimulus; Stress; Testing; Therapeutic; Tissues; Translating; Treatment Efficacy; Warburg Effect; adduct; aerobic glycolysis; antimicrobial; cytokine; evidence base; functional plasticity; glucose transport; glycation; in vivo; inorganic phosphate; mitochondrial dysfunction; mitochondrial metabolism; new therapeutic target; novel; novel therapeutics; overexpression; pathogen; prevent; programs; response; septic patients; therapeutic evaluation; transcription factor

Sepsis is an aberrant immune response to infection1 with approximately one million cases/year in the U.S.A. and an overall fatality rate of ~20-30%, increasing to ~40-50% in the case of septic shock1-3. Sepsis is characterized by stress hyperglycemia4, mitochondrial dysfunction5, and persistent, strongly oxidizing conditions. Although sepsis is a complex disease involving many different cells and tissues, a better understanding of the role of macrophages (Mf) during sepsis may reveal new therapeutic targets. Mf exhibit dynamic, stimulus-dependent functional plasticity in vitro and in vivo and critical changes to their activities during sepsis are thought to be initiated by bacterial products (e.g., lipopolysaccharide; LPS) and proinflammatory cytokines (e.g., interferon-g; IFN-g) that reprogram Mf to a highly proinflammatory, “classically activated” or “M1” phenotyperev. in 6. These signaling pathways also stabilize the transcription factor Hypoxia- Inducing Factor-1a (HIF-1a)7,8. HIF-1a is a master regulator of glycolytic genes9, facilitating a profound “metabolic switch,” the “Warburg effect” rev. in 10-12, in M1 Mf in which glycolysis predominates and mitochondrial oxidative phosphorylation is essentially absent, even when oxygen is present. We propose that this metabolic dysregulation underlies inflammation during sepsis, by driving production of proinflammatory cytokines as well as exposure of tissues to damaging M1 Mf-dependent reactive oxygen species (ROS), proteases, and bioactive lipids. While cytokines and ROS have been extensively studied, less is known about the role of methylglyoxal (MG), a highly reactive, dicarbonyl byproduct that can accumulate intracellularly during the glycolytic reaction mediated by triose phosphate isomerase (TPI)14,15. Significantly, elevated MG in sera of septic shock patients has been identified as a biomarker that correlates with disease severity21. We have reported that MG accumulates in M1 Mf upon stimulation with LPS and IFN-g in vitro, and results in the formation of covalent “MG-adducts” with host proteins both in vitro and in the lungs of endotoxic mice17. Our central hypothesis is that MG, a relatively short-lived, but highly reactive metabolite generated in response to LPS+IFN-g activation of Mf, directs inflammatory M1 Mf differentiation in sepsis, and that strategies that inhibit MG production or activity will prevent such differentiation, and thereby reduce Mf-directed inflammation. Our scientific premise is that selective targeting of MG accumulation can be capitalized upon to mitigate sepsis- associated tissue damage and death. We propose that LPS + IFN-g-induced stabilization of HIF-1a initiates sepsis by promoting M1 Mf differentiation through increased glycolysis, MG accumulation, MG-mediated glycation of mitochondrial proteins that disrupts mitochondrial function. Specific Aim 1 will characterize mechanisms by which MG accumulation in Mf disrupts mitochondrial function, Aim 2 will examine the role of metabolic signaling pathways on MG accumulation, and Aim 3 will test the therapeutic efficacy of MG- degrading enzymes to mitigate endotoxicity and bacterial sepsis.

脓毒症是一种对感染的异常免疫反应，在美国每年约有100万例