Macrophage immunometabolism controls septic shock

巨噬细胞免疫代谢控制感染性休克

• 批准号: 10658162
• 负责人: Ivan Zanoni
• 金额: $ 63.15万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-22 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658162
• 关键词: AKT inhibition; Affect; Anti-Inflammatory Agents; Bacteremia; Binding; Biochemistry; Cells; Cessation of life; Complex; Country; Data; Development; EZH2 gene; Endotoxic Shock; Environment; Epigenetic Process; Equilibrium; Extracellular Space; FDA approved; Genes; Genetic Transcription; Goals; Gram-Negative Bacteria; Histone H3; Homeostasis; Human; Immune; Immune response; Immune system; In Vitro; Inflammasome; Inflammation; Inflammatory; Injury; Innate Immune System; Interleukin-1 beta; Interleukin-10; Intervention; Knockout Mice; Ligands; Lipopolysaccharides; Lysine; Macrophage; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methionine; Mitochondria; Modification; Molecular; Mus; Pathology; Pattern; Pattern Recognition; Pattern recognition receptor; Phagocytes; Pharmaceutical Preparations; Phase; Phospholipids; Phosphorylcholine; Play; Process; Production; Proto-Oncogene Proteins c-akt; Recovery; Role; Sepsis; Septic Shock; Signal Transduction; Site; Solid; Sterility; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Work; conditional knockout; cytokine; empowerment; enzyme activity; epigenomics; forging; histone methylation; immunoregulation; in vivo; in vivo evaluation; innovation; metabolic profile; metabolomics; microbial; mouse model; novel; novel therapeutic intervention; oxidation; oxidized phosphatidyl choline; pathogen; polymicrobial sepsis; prevent; therapeutic target; therapeutically effective; tissue injury

Inflammation evolved to lead to recovery from sterile or microbial injuries. The induction of the inflammatory process not only activates the immune cells, but also alters their metabolism and thus forge the immune response. Accumulating evidence shows that a proper inflammatory process requires the coincident recognition by pattern recognition receptors (PRRs) of exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). We recently demonstrated that the coincident recognition of lipopolysaccharide (LPS), the major component of Gram-negative bacteria, and host-derived oxidized phospholipids known as oxPAPC (a class of DAMPs) leads to the formation of phagocytes characterized by a unique metabolic profile that increases the production of interleukin (IL)-1β, a potent pro-inflammatory cytokine. Whether, and how, the simultaneous encounter of LPS and oxPAPC alters other inflammatory activities of phagocytes remains largely unknown. Based on new compelling data, here we hypothesize that the coincident recognition of LPS and oxPAPC alters key metabolic checkpoints to drive hyper-inflammation. Also, that these changes can be harnessed against septic shock. Sepsis is a complex inflammatory syndrome characterized by a hyper-inflammatory phase called septic shock. Although it was previously proposed that oxPAPC protects against the hyperinflammatory phase of sepsis by inhibiting the capacity of LPS to signal, our new unpublished data show instead that oxPAPC production follows LPS or bacterial encounter in vivo and that oxPAPC increases inflammation and lethality in mouse models of sepsis. Notably, we found that, to exert its functions, oxPAPC directly interacts with, and inhibits, AKT. AKT is a central metabolic checkpoint that regulates the metabolism of phagocytes and their inflammatory activity. AKT inhibition by oxPAPC prevents the production of IL-10. IL-10 is a pluripotent immunoregulatory cytokine indispensable for maintaining immune homeostasis and restricting inflammation during sepsis. Mechanistically, oxPAPC-dependent inhibition of AKT potentiates the methionine cycle and favors the trimethylation of the histone H3, thus switching off IL-10 transcription. Supported by our new solid data, we will employ biochemistry, transcriptional and epigenetic analyses, as well as metabolomics in vitro to further dissect the signaling cascade initiated by oxPAPC during LPS encounter. By using new transgenic or conditional knock-out mice, as well as commercially available drugs, we will test in vivo the possibility to target the newly identified metabolic pathways regulated by oxPAPC to protect against sepsis. Altogether we will characterize the molecular components that mediate host-derived inflammatory ligand-dependent immunometabolic functions. Our study will offer potential therapeutic targets for modulating immune system activation and sepsis, a devastating inflammatory syndrome that is widespread in western countries.

炎症的发展导致了无菌或微生物损伤的恢复。炎症过程的诱导不仅激活免疫细胞，而且改变它们的代谢，从而形成免疫应答。越来越多的证据表明，一个适当的炎症过程需要模式识别受体（PRR）的外源性病原体相关分子模式（PAMPs）和内源性损伤相关分子模式（DAMPs）的一致识别。我们最近证明，脂多糖（LPS）（革兰氏阴性菌的主要成分）和宿主来源的氧化磷脂（称为oxPAPC，一类DAMP）的同时识别导致吞噬细胞的形成，其特征在于独特的代谢特征，可增加白细胞介素（IL）-1β（一种强效促炎细胞因子）的产生。是否，以及如何同时遇到LPS和oxPAPC改变吞噬细胞的其他炎症活动仍然在很大程度上未知。基于新的令人信服的数据，在这里我们假设LPS和oxPAPC的同时识别改变了关键的代谢检查点，以驱动过度炎症。同时，这些变化可以用来对抗感染性休克。脓毒症是一种复杂的炎症综合征，其特征在于称为脓毒性休克的高度炎症阶段。尽管之前提出oxPAPC通过抑制LPS信号传导能力来防止脓毒症的过度炎症阶段，但我们新的未发表的数据显示，oxPAPC的产生是在体内LPS或细菌相遇后产生的，并且oxPAPC增加了脓毒症小鼠模型的炎症和致死性。值得注意的是，我们发现，为了发挥其功能，oxPAPC直接与AKT相互作用并抑制AKT。AKT是调节吞噬细胞代谢及其炎症活性的中心代谢检查点。oxPAPC对AKT的抑制可阻止IL-10的产生。IL-10是一种多能性免疫调节细胞因子，在脓毒症期间维持免疫稳态和限制炎症不可或缺。从机制上讲，oxPAPC依赖性抑制AKT增强甲硫氨酸循环，有利于组蛋白H3的三甲基化，从而关闭IL-10转录。在我们新的坚实数据的支持下，我们将采用生物化学，转录和表观遗传分析，以及体外代谢组学，以进一步剖析LPS相遇过程中oxPAPC启动的信号级联反应。通过使用新的转基因或条件性基因敲除小鼠，以及市售药物，我们将在体内测试靶向oxPAPC调节的新鉴定的代谢途径以防止败血症的可能性。总之，我们将表征介导宿主源性炎症配体依赖性免疫代谢功能的分子组分。我们的研究将为调节免疫系统激活和脓毒症提供潜在的治疗靶点，脓毒症是一种在西方国家广泛存在的毁灭性炎症综合征。