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Phd2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses

Research output: Contribution to journalArticle

  • Joseph A Willson
  • Fiona Murphy
  • Amy Lewis
  • David Sammut
  • Emily Watts
  • A A Roger Thompson
  • Helen M. Marriott
  • Cormac T. Taylor
  • Martin Schneider
  • Patrick H Maxwell
  • Peter J Ratcliffe
  • Christopher J Schofield
  • Bart Ghesquiere
  • Peter Carmeliet

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Original languageEnglish
JournalJournal of Clinical Investigation
Early online date14 Aug 2017
DOIs
Publication statusPublished - Sep 2017

Abstract

Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential to limit tissue damage. Here we identify a critical role for Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 results in an exaggerated inflammatory response to S. pneumonia with increases in neutrophil motility, functional capacity and survival. These enhanced neutrophil responses are dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicates the Phd2-deficient phenotype of delayed inflammation resolution. Together these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils in normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease.

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