Arthritis as a model to define immunometabolism pathways to control inflammation

多形核中性粒细胞（PMNs）在生理和病理中发挥着重要作用，但我们对PMNs执行这些功能的代谢要求知之甚少。我的项目使用抗原诱导的小鼠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在激活、迁移和存活中的功能，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）确定是否可以通过靶向PMN能量代谢来调节炎症。最近的研究揭示了关于免疫代谢的新信息，免疫代谢被定义为免疫细胞内代谢途径的变化，改变了它们的功能。这些研究表明，淋巴细胞、巨噬细胞和树突状细胞在环境变化（如缺氧或营养可用性）的反应中经历了深刻的代谢重编程，但重要的是在对促炎性和抗炎性介质的反应中也发生了重编程。然而，这些研究大多是在体外进行的；尽管在高度控制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，将pmn简单地归类为预先到达并执行此功能的抗微生物细胞，在考虑免疫代谢时经常被忽视或忽略，需要重新评估其位置。从血流中招募pmn来执行效应功能。pmn的募集是由细胞粘附分子调控的，细胞粘附分子最初导致pmn在内皮上滚动。滚动是必要的随后牢固粘附的pmn到容器。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。PMNs在组织中发挥效应作用后，通过细胞凋亡促进炎症的消退。然而，如果PMN功能上调，它们有可能引起不希望的宿主组织损伤。另一方面，如果PMN功能下调，宿主可能容易受到感染。因此，PMN功能的微调必须伴随着代谢的微调。我的项目将解决PMN在体内系统中与炎症反应的启动、持续和消退相关的免疫代谢微调方面的重大知识空白。

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.