Targeting macrophage maladaptation for bacterial sepsis treatment

针对细菌性脓毒症治疗的巨噬细胞适应不良

• 批准号: 10759684
• 负责人: Xuewei Zhu
• 金额: $ 30万
• 依托单位: ACEPRE, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759684
• 关键词: Acute; Adrenal Cortex Hormones; Animal Model; Anti-Inflammatory Agents; Antibiotics; Attention; Attenuated; Back; Bacteremia; Biochemical; Biological Availability; Bone Marrow; Brain; Cell Death; Cells; Cultured Cells; Cyclic GMP; Data; Dendritic Cells; Development; Dichloroacetate; Disease; Dose; Drug Kinetics; Economic Burden; Effectiveness; Energy Supply; Family suidae; Female; Formulation; Generations; Glycolysis; Health; Heart; Hepatocyte; Heterogeneity; Histologic; Human; Immune; Immune system; Immunocompetence; Immunosuppression; In Vitro; Inbreeding; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Invaded; Investigational Drugs; Kidney; Life; Liver; Macrophage; Measurement; Mediating; Metabolic; Microbe; Mitochondria; Modeling; Molecular; Mononuclear; Mouse Strains; Mus; Nigericin; Organ; Outcome; Oxidative Phosphorylation; Oxidative Stress; PDH kinase; Paralysed; Pathway interactions; Pattern; Phagocytes; Phase; Plasma; Play; Process; Production; Proteins; Pyruvate; Reactive Oxygen Species; Regimen; Resolution; Role; Safety; Sepsis; Shock; Small Business Technology Transfer Research; Societies; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Toll-like receptors; Toxic effect; Toxicity Tests; Vascular Endothelial Cell; analog; anergy; cecal ligation puncture; effective therapy; efficacy evaluation; fighting; improved; in vivo; individual patient; inhibitor; male; manufacture; marenostrin; metabolic fitness; mitochondrial dysfunction; mouse model; novel therapeutics; organ regeneration; oxidative damage; pathogen; phase 2 study; pre-clinical; receptor; safety testing; secondary infection; septic patients; small molecule

Summary. Sepsis results in massive loss of life and places a significant economic burden on society. There are no effective treatments available for human sepsis other than antibiotics and life support. It is increasingly clear that sepsis is a bi-phasic process comprised of 1) an early high-energy demanding hyperinflammation state that can cause inflammatory shock and 2) a low energy supply immunosuppression state that promotes immunometabolic paralysis while countering oxidative damage. These two phases are seamlessly connected or even concurrent. This makes sepsis treatment extremely difficult, and many therapies such as anti- inflammatory corticosteroids often worsen the outcome. Macrophages (MΦs) play essential roles throughout the course of sepsis. In the hyperinflammation phase, MΦs sense pathogen-associated molecular patterns (PAMPs) through receptors such as toll-like receptors (TLRs) and NOD-, LRP-, and pyrin domain-containing protein 3 (NLRP3). MΦ NLRP3 inflammasome activation and resulting IL-1β secretion cause acute organ damage and release of damage-associate molecular patterns (DAMPs), which act back on the inflammatory pathways, forming a vicious cycle. Therefore, the MΦ NLRP3 inflammasome is a major contributor to the hyperinflammation phase of bacterial sepsis. Concomitant with inflammasome activation, MΦs undergo a broad cellular metabolic rewiring that favors glycolysis and turns mitochondria from ATP generation to reactive oxygen species (ROS) production, leading to mitochondrial oxidative stress, metabolic paralysis, and MΦ anergy in the immunosuppression phase. In addition, NLRP3 inflammasome activation results in GSDMD- mediated pyroptotic cell death (pyroptosis), directly removing MΦs from the fight against secondary infections. Recently, we identified that in MΦs, pyruvate dehydrogenase kinase 1 (PDHK1) plays a critical role in coordinating inflammasome activation and metabolic rewiring. In MΦs treated with LPS and ATP or Nigericin to stimulate inflammasome activation, dichloroacetate (DCA, a pyruvate analog and pan-PDHK inhibitor) or JX06 (a synthetic small-molecule and selective PDHK1 inhibitor) effectively suppressed IL-1β secretion and cell death, improved mitochondrial integrity, and reprogramed mitochondria from ROS production to ATP generation. In a mouse cecal ligation and puncture (CLP) model, PDHK inhibition significantly reduced plasma IL-1β levels. In this STTR Phase 1 project, we will test the hypothesis that JX06 can be developed as a novel therapy for bacterial sepsis. We propose two specific aims: SA1. To determine the toxicity of JX06 in cultured primary mouse and human cells in vitro and mice in vivo, and to study its pharmacokinetics in mice. SA2. To establish the effectiveness of JX06 in various mouse strains using the CLP model of sepsis. This STTR Phase 1 project will validate the role of MΦ PDHK1 in bacterial sepsis and provide a proof of concept to develop JX06 or its analog as a new therapeutic agent for bacterial sepsis. The successful completion of these proposed studies will serve as a milestone for the further development effort.

概括。败血症会导致生命的巨大损失，并对社会造成了巨大的经济燃烧。那里 除抗生素和生命支持外，没有其他可用于人类败血症的有效治疗方法。它越来越多 清楚地表明，败血症是一个双重过程完成1）早期高能要求超炎症 可能引起炎症性休克的状态和2）促进的低能量供应免疫抑制状态 免疫代谢瘫痪，同时应对氧化损伤。这两个阶段是无缝连接的 甚至并发。这使脓毒症的治疗极为困难，许多疗法，例如 炎性皮质类固醇通常会担心结果。巨噬细胞（mφs）在整个过程中扮演重要角色 败血症的过程。在高炎阶段，MφS觉得病原体相关的分子模式 （PAMP）通过受体，例如Toll样受体（TLR）和NOD-，LRP-和含吡啶结构域的受体 蛋白3（NLRP3）。 MφNLRP3炎性体激活和由此产生的IL-1β分泌引起急性器官 损伤和释放损害缔合分子模式（抑制作用），对炎症作用 途径，形成一个恶性循环。因此，MφNLRP3炎性体是造成这种情况的主要因素 细菌败血症的高炎阶段。与炎性体激活同时，Mφ经历A 广泛的细胞代谢重新布线有利于糖酵解并将线粒体从ATP产生转化为反应性 氧（ROS）产生，导致线粒体氧化物应激，代谢瘫痪和Mφ 在免疫抑制阶段的消极。此外，NLRP3炎性体激活导致GSDMD- 介导的凋亡细胞死亡（凋亡），直接从与继发感染的斗争中取出Mφ。 最近，我们确定在MφS中，丙酮酸脱氢酶激酶1（PDHK1）在 协调炎症体激活和代谢重新布线。在用LPS和ATP或Nigeryin处理的MφS中 刺激炎性体激活，二氯乙酸（DCA，丙酮酸类似物和PAN-PDHK抑制剂）或JX06 （一种合成的小分子和选择性PDHK1抑制剂）有效抑制IL-1β分泌和细胞 死亡，改善线粒体完整性以及从ROS产生到ATP的重新编程的线粒体 一代。在小鼠盲肠连接和穿刺（CLP）模型中，PDHK抑制显着降低了等离子体 IL-1β水平。在这个STTR 1阶段项目中，我们将测试可以开发JX06作为新颖的假设 败血症细菌的治疗。我们提出了两个具体目标：SA1。确定JX06在培养中的毒性 原代小鼠和人类细胞在体内和小鼠体内，并研究其在小鼠中的药代动力学。 SA2。到 使用败血症的CLP模型确定JX06在各种小鼠菌株中的有效性。这个sttr阶段 1项目将验证MφPDHK1在细菌败血症中的作用，并提供概念证明以发展JX06 或其作为败血症细菌的新治疗剂的类似物。这些建议的成功完成 研究将成为进一步发展努力的里程碑。