Regulation of tissue neutrophil function and survival by the interplay between oxygen and metabolite sensing pathways

Neutrophils are essential for host defence but widely implicated in disease. A fine balance exists between maintaining effective host pathogen responses and limiting host-mediated tissue damage. Innate responses to bacterial challenge are critically regulated by oxygen availability. We have implicated different components of the HIF/hydroxylase pathway in regulating these outcomes. We also showed exposure to hypoxia can reprogramme subsequent neutrophil responses to infection. More recently, we observed that changes in oxygen availability and HIF/hydroxylase activity are associated with alterations in neutrophil metabolic status. I propose that neutrophil adaptation to oxygen and nutrient deprivation at inflamed sites is a consequence of interplay between HIF/hydroxylase activity and metabolic specialization, which defines the magnitude and duration of the neutrophilic response. The goals of this proposal are therefore to: 1. Define the mechanisms by which hypoxia reprogrammes the inflammatory response. 2. Dissect the mechanisms by which HIF/hydroxylase pathway members regulate neutrophil metabolism and subsequent biological function. The ultimate goal is to identify tissue-specific factors that can be targeted to limit detrimental inflammation whilst preserving systemic immunity. This is an area of significant clinical need, with no current strategies that target neutrophil mediated inflammation either in the context of sepsis or chronic inflammatory disease.