Sarah Walmsley (Affiliate)

Research in a Nutshell

Hypoxia and limited nutrient availability frequently characterize the inflammatory site.  My work has focused on understanding the importance of hypoxia, metabolic adaptations and the oxygen sensing HIF/hydroxylase pathway in defining outcomes of neutrophilic inflammation in the context of host pathogen responses, and more recently in the cancer niche.  This work has resulted in three inter-related observations and future programs of work.

1. Interaction between hypoxia and the host response

Our group is exploring the interaction between hypoxia and the host response.  This is important because hypoxia and bacterial infection frequently co-exist and are associated with adverse outcomes.  In the context of acute hypoxia, both local bacterial infection and systemic infection results in rapidly progressive neutrophil-mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise.  This response is ameliorated by prior exposure of animals.  How hypoxia preconditions the neutrophil response remains an area of considerable research interest.

2. Regulation of neutrophil survival and function by the HIF/hydroxylase pathway

Unique to the neutrophil hypoxia is a profound survival stimulus. Neutrophils both sense oxygen and respond to changes in oxygenation via the HIF pathway, which involves regulation of the transcription factor hypoxia inducible factor (HIF) by von Hippel Lindau protein and a group of oxygen sensitive hydroxylases – prolyl hydroxylase domain (PHD) containing enzymes and factor inhibiting HIF (FIH). A greater understanding of the mechanisms by which the members of his oxygen sensitive pathway regulate neutrophil responses in health and disease states will be critical in developing strategies to limit neutrophilic inflammation.

3. Metabolic specialisation of neutrophils

Neutrophils demonstrate metabolic adaptations that enable them to function at sites of limited oxygen availability for example in the cancer niche.  How interplay between oxygen sensing responses and metabolite utilization define neutrophil activation, function and survival both during acute inflammatory responses and in both local and metastatic cancer niches remains to be explored.

Contact

Sarah.walmsley@ed.ac.uk

Collaborations

• Professor Ratcliffe and Professor Pugh, University of Oxford
• Professor Schofield, University of Oxford
• Professor Cantrell, University of Dundee
• Professor Dockrell, University of Edinburgh
• Professor Carmeliet, VIB and KU Leuven
• Professor Mazzone, VIB and KU Leuven

Partners and Funders

• Wellcome Trust
• Medical Research Council
• CRUK