Arthritis as a model to define immunometabolism pathways to control inflammation

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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.*****