Macrophage immunometabolism controls septic shock

巨噬细胞免疫代谢控制感染性休克

基本信息

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
项目类别：
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

项目摘要

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.

炎症的进化导致无菌或微生物损伤的恢复，炎症过程的诱导不仅会激活免疫细胞，而且会改变它们的新陈代谢，从而形成免疫反应。越来越多的证据表明，适当的炎症过程需要免疫细胞的一致识别。我们最近证明了外源病原体相关分子模式（PAMP）和内源损伤相关分子模式（DAMP）的模式识别受体（PRR）的一致识别。脂多糖 (LPS) 是革兰氏阴性细菌的主要成分，而宿主衍生的氧化磷脂（称为 oxPAPC）（一类 DAMP）会导致吞噬细胞的形成，其特征是具有独特的代谢特征，可增加白细胞介素 (IL) 的产生-1β，一种有效的促炎细胞因子。LPS 和 oxPAPC 的同时相遇是否以及如何改变吞噬细胞的其他炎症活动仍然很大程度上未知。数据显示，LPS 和 oxPAPC 的同时识别会改变关键的代谢检查点以驱动过度炎症，而且，这些变化可以用来对抗感染性休克，这是一种复杂的炎症综合征，其特征是称为脓毒症的高炎症阶段。尽管之前有人提出 oxPAPC 通过抑制 LPS 发出信号的能力来预防脓毒症的高炎症阶段，但我们新的未发表的数据表明 oxPAPC 的产生遵循 LPS。值得注意的是，为了发挥其功能，oxPAPC 直接与 AKT 相互作用并抑制 AKT 的代谢。 oxPAPC 抑制吞噬细胞及其炎症活性可阻止 IL-10 的产生，IL-10 是维持免疫系统所必需的多能免疫调节细胞因子。从机制上讲，oxPAPC 依赖性的 AKT 抑制会增强蛋氨酸循环并有利于组蛋白 H3 的三甲基化，从而关闭 IL-10 转录。在我们新的可靠数据的支持下，我们将采用生物化学、转录和通过使用新的转基因技术，进行表观遗传学分析以及体外代谢组学，以进一步剖析 oxPAPC 在 LPS 遭遇过程中引发的信号级联反应。或条件性基因敲除小鼠，以及市售药物，我们将在体内测试针对新发现的由 oxPAPC 调节的代谢途径以预防脓毒症的可能性。我们的研究将为调节免疫系统激活和败血症（一种在西方国家普遍存在的破坏性炎症综合征）提供潜在的治疗靶点。