Macrophage Metabolism After Target Cell Ingestion Regulates Anti-Inflammatory Reprogramming

靶细胞摄入后巨噬细胞代谢调节抗炎重编程

• 批准号: 10460503
• 负责人: Alexandra Leigh McCubbrey
• 金额: $ 24.9万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460503
• 关键词: Acute; Address; Advisory Committees; Affect; Amino Acids; Anti-Inflammatory Agents; Apoptotic; Arginine; Biology; Bone Marrow; Cells; Chimera organism; Data; Development; Dose; Enzymes; Evaluation; Failure; Foundations; Genetic Transcription; Human; Immune; In Vitro; Inflammasome; Inflammation; Inflammatory; Ingestion; Injury; Interleukin-1 beta; Investigation; Isotopes; Journals; Knowledge; Laboratories; Learning; Leukocytes; Lung diseases; Measures; Mediating; Mentors; Metabolic; Metabolism; Molecular Target; Mus; Necrosis; Pharmacology; Phase; Polyamines; Process; Production; Pulmonary Inflammation; Putrescine; Reporting; Research; Resolution; Role; Scientist; Signal Transduction; Source; Spermidine; Spermine; System; Techniques; Testing; Transgenic Organisms; Up-Regulation; Work; arginase; congenic; cytokine; experience; histone methylation; histone modification; in vivo; inhibitor; lung injury; lung repair; macromolecule; macrophage; metabolomics; monocyte; prevent; pulmonary function; recruit; response; restoration; symposium; transcriptome sequencing

ABSTRACT Inflammation is a ubiquitous component of lung disease involving accumulation of leukocytes in the airspaces. In order for inflammation to resolve, dead and dying leukocytes must be removed and production of inflammatory cytokines must be turned off. Macrophages (Mϕ) are key orchestrators of these processes, however the triggers that reprogram inflammatory Mϕ to perform these roles remain incompletely understood. Clearance of dead cells has been shown to provide an important reprogramming signal, but we have limited knowledge of the precise mechanisms by which dead cell ingestion facilitates redirection of Mϕ function. Recent work has demonstrated a key role for cellular metabolism in determining Mϕ function. Ingested target cells provide a clear source of varied macromolecules that must be digested by Mϕ. However, little research has been done to assess intracellular metabolites produced by this process or to consider the subsequent immune consequence. We propose the first comprehensive study of Mϕ metabolism following target cell ingestion and degradation, and hypothesize that changes in the levels of intracellular metabolites control ingestion-driven Mϕ reprogramming. Our preliminary studies have identified a promising molecular target, polyamines, which are dramatically increased in Mϕ following the ingestion of apoptotic target cells. Polyamines have a known anti- inflammatory function including suppression of numerous pro-inflammatory cytokines. We propose to test the hypothesis that upregulation of polyamine synthesis by Mϕ following target cell ingestion is critical to suppress a key Mϕ cytokine IL-1β, and important for the resolution of lung inflammation in vivo. During the K99 mentored phase, I will build upon my experience studying Mϕ biology and target cell clearance by learning techniques related to cellular metabolism including unbiased metabolomics and the use of isotope metabolites to measure metabolic flux. During this phase, I will: 1) complete a comprehensive, integrated assessment of the metabolites produced following ingestion of target cells, focusing on polyamines, and assess whether these metabolites derive from digested target cell material, and 2) specifically assess the role of arginase-1 in regulating polyamine synthesis by inflammatory Mϕ. Simultaneously, I will enrich my professional development by participating in journal clubs, seminars, national conferences, coursework, and having semi-annual evaluations by a trainee advisory committee. The R00 independent phase will allow me to establish my laboratory as I continue investigation into: 3) how Mϕ polyamines affect cytokine production after target cell ingestion, and 4) the effects of Mϕ polyamines on resolution of inflammation and lung repair. Collectively, this proposal will enhance my current expertise, address a critical unknown in the field of target cell clearance, and provide the necessary foundation to establish myself as an independent research scientist.

抽象的 炎症是涉及白细胞中肺部疾病的普遍成分 空间。为了解决炎症，必须去除死亡和垂死的白细胞 炎症性细胞因子必须关闭。 然而，重编程发炎的触发器执行这些角色角色的触发因素仍未完全理解。 死细胞的清除是为了提供重要的报告信号，但是我们有限 了解死细胞摄入的精确机制有助于重定向M函数。 最近的工作表明了细胞代谢在确定Mϕ功能中的关键作用。 细胞提供了不同的大分子的清晰来源，但很少有研究 已经进行了评估该过程产生的细胞内代谢产物或考虑随后的 免疫解决方案。 我们提出了目标细胞摄入后M代谢的首次全面研究， 降解，并假设细胞内代谢产物控制摄入驱动的M ϕ的水平的变化 重新摄影。我们的预后研究已经确定 摄入凋亡的靶细胞后，Mϕ的急剧增加。 我们建议测试您。 假设是，靶细胞摄入后M ϕ上调多胺合成对于抑制至关重要 关键的M ϕ细胞因子IL-1β，对于在体内肺部炎症的分辨率很重要。 在K99指导阶段，我将基于研究M ϕ生物学和靶细胞的经验 通过学习技术与细胞代谢有关的清除技术，包括无偏代谢组学和使用 同位素代谢物的测量代谢通量。 摄入靶细胞后产生的代谢产生的代谢产物的综合评估，重点是多胺， 并评估这些代谢产物是否来自消化的靶细胞材料，2）专门评估 精氨酸酶-1在炎症M ϕ调节多胺合成中的作用。 通过参加期刊俱乐部，研讨会，全国会议，课程工作以及 由培训咨询委员会进行半年度评估。 当我继续调查以下情况时，请建立我的实验室：3）M ϕ多胺如何影响细胞因子的产生 靶细胞摄入，4）M ϕ多胺对炎症和肺修复的分辨率的影响。 总的来说，该建议将通过增强我当前的专业知识，解决目标领域的关键未知 细胞清除，并为将自己确立为独立研究科学家提供必要的基础。