Understanding hypoxic and inflammatory reprogramming of neutrophil responses to inform anti-inflammatory strategies

Year of award: 2022

Grantholders

  • Prof Sarah Walmsley

    University of Edinburgh, United Kingdom

Project summary

Neutrophils have adapted to function in injured and infected tissues where oxygen and metabolites are limited. A proportionate neutrophil response is essential for effective immunity, with dysregulated neutrophilic inflammation contributing to the pathogenesis of inflammatory disease states. In the lung, dysfunctional neutrophilic inflammation can result in the development of acute respiratory distress syndrome, with the associated systemic hypoxia contributing to tissue hypoxia. My group has observed that not only does local hypoxia in the inflamed environment alter neutrophil behaviour, but also that systemic hypoxia can shape neutrophil responses with consequence for inflammation outcomes. We have emerging evidence that despite a short half-life, some of these changes in neutrophil physiology are long-lasting. This has led me to propose that systemic hypoxia drives central (bone marrow) epigenetic changes within neutrophil progenitors which are inherited by newly differentiated neutrophils and sustained long after the initial exposure. I further propose this central reprogramming can be informed by local cues following an inflammatory insult, with consequence for tissue effector functions and inflammation outcomes. The key goal of this proposal is to understand how activation of oxygen sensing pathways, metabolic processes and chromatin accessibility reprogram neutrophil responses and identify new targets to treat dysfunctional neutrophilic inflammation.