Arthritis as a model to define immunometabolism pathways to control inflammation

关节炎作为定义控制炎症的免疫代谢途径的模型

• 批准号: RGPIN-2019-04459
• 负责人: Lopes, Fernando
• 金额: $ 2.4万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684540
• 关键词: Arthritis; model; define; immunometabolism; pathways

Polymorphonuclear neutrophils (PMNs) play critical functions in physiology and pathology, but we poorly understand the metabolic requirements for PMNs to perform these functions. My program uses the model of antigen-induced arthritis in mice to investigate the concept that the balance of energy metabolism between glycolysis and oxidative phosphorylation (OXPHOS) governs PMN functions in activation, migration and survival, processes that contribute to the effectiveness, duration and outcome of the inflammatory response. A structured series of hypothesis-driven experiments will be performed to (i) advance knowledge of metabolic pathways used by PMNs in migration and during resolution of inflammation; and (ii) determine if inflammation can be modulated by targeting PMN energy metabolism.******Recent studies have revealed new information about immunometabolism, defined as changes in intracellular metabolic pathways in immune cells that alter their function. These studies indicated that lymphocytes, macrophages and dendritic cells undergo profound metabolic reprogramming in response to environmental changes, such as hypoxia or nutrient availability, but importantly also in response to pro- and anti-inflammatory mediators. However, most of these studies were conducted in vitro; despite providing results in a highly controlled environment, the in vitro milieu does not represent the complete physiological environment. In addition, based on classification simply as an anti-microbial cell that arrives pre-armed to perform this function, PMNs are often overlooked or dismissed when considering immunometabolism, and this position needs to be re-evaluated.******PMNs are recruited from the bloodstream to perform effector functions. Recruitment of PMNs is regulated by cell adhesion molecules that initially lead to the rolling of PMNs on the endothelium. Rolling is imperative to the subsequent firm adhesion of PMNs to the vessel. Once adhered, PMNs initiate a crawling movement that leads to the emigration of those cells from the blood to tissue. After performing effector functions in the tissue, PMNs undergo apoptosis to promote the resolution of inflammation. However, if PMN function is upregulated, they have the potential to cause undesired host tissue damage. On the other hand, if PMN function is downregulated, the host may become susceptible to infections. Therefore, fine-tuning of PMN function must be accompanied by metabolic fine-tuning. My program will address significant gaps in knowledge around fine-tuning of immunometabolism in PMN in an in vivo system relevant to the initiation, duration and resolultion of the inflammatory response.*****

多形核中性粒细胞（polymorphisms neutrophil，PMNs）在生理和病理中起着重要的作用，但人们对PMNs发挥这些作用的代谢要求知之甚少。我的程序使用小鼠抗原诱导的关节炎模型来研究糖酵解和氧化磷酸化（OXPHOS）之间的能量代谢平衡控制PMN激活，迁移和存活功能的概念，这些过程有助于炎症反应的有效性，持续时间和结果。将进行一系列结构化的假设驱动实验，以（i）推进PMN在迁移和炎症消退过程中使用的代谢途径的知识;（ii）确定炎症是否可以通过靶向PMN能量代谢来调节。最近的研究揭示了关于免疫代谢的新信息，免疫代谢被定义为改变免疫细胞功能的细胞内代谢途径的变化。这些研究表明，淋巴细胞，巨噬细胞和树突状细胞经历了深刻的代谢重编程，以响应环境变化，如缺氧或营养物质的可用性，但重要的是也响应促炎和抗炎介质。然而，这些研究中的大多数是在体外进行的;尽管在高度受控的环境中提供了结果，但体外环境并不代表完整的生理环境。此外，基于简单地分类为预先武装以执行此功能的抗微生物细胞，在考虑免疫代谢时，PMN经常被忽视或忽略，这一立场需要重新评估。PMN从血流中募集以执行效应器功能。PMN的募集受细胞粘附分子的调节，细胞粘附分子最初导致PMN在内皮上滚动。滚动对于PMN随后与血管的牢固粘附是必不可少的。一旦粘附，PMN开始爬行运动，导致这些细胞从血液迁移到组织。在组织中执行效应器功能后，PMN经历凋亡以促进炎症的消退。然而，如果PMN功能上调，它们有可能导致不希望的宿主组织损伤。另一方面，如果PMN功能下调，宿主可能变得对感染易感。因此，PMN功能的微调必须伴随着代谢微调。我的计划将解决在与炎症反应的启动，持续时间和消退相关的体内系统中PMN免疫代谢微调方面的知识空白。