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Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish

Research output: Contribution to journalArticlepeer-review

  • A. A. Roger Thompson
  • Philip M. Elks
  • Helen M. Marriott
  • Suttida Eamsamarng
  • Kathryn R. Higgins
  • Amy Lewis
  • Lynne Williams
  • Selina Parmar
  • Gary Shaw
  • Emmet E. McGrath
  • Federico Formenti
  • Fredericus J. Van Eeden
  • Vuokko L. Kinnula
  • Christopher W. Pugh
  • Ian Sabroe
  • Edwin R. Chilvers
  • Peter A. Robbins
  • Melanie J. Percy
  • M. Celeste Simon
  • Randall S. Johnson
  • Stephen A. Renshaw

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)366-376
Number of pages11
JournalBlood
Volume123
Issue number3
Early online date6 Nov 2013
DOIs
Publication statusPublished - 16 Jan 2014

Abstract

Neutrophil lifespan and function are regulated by hypoxia via components of the hypoxia inducible factor (HIF)/von Hippel Lindau/hydroxylase pathway, including specific roles for HIF-1α and prolyl hydroxylase-3. HIF-2α has both distinct and overlapping biological roles with HIF-1α and has not previously been studied in the context of neutrophil biology. We investigated the role of HIF-2α in regulating key neutrophil functions. Human and murine peripheral blood neutrophils expressed HIF-2α, with expression up-regulated by acute and chronic inflammatory stimuli and in disease-associated inflammatory neutrophil. HIF2A gain-of-function mutations resulted in a reduction in neutrophil apoptosis both ex vivo, through the study of patient cells, and in vivo in a zebrafish tail injury model. In contrast, HIF-2α–deficient murine inflammatory neutrophils displayed increased sensitivity to nitrosative stress induced apoptosis ex vivo and increased neutrophil apoptosis in vivo, resulting in a reduction in neutrophilic inflammation and reduced tissue injury. Expression of HIF-2α was temporally dissociated from HIF-1α in vivo and predominated in the resolution phase of inflammation. These data support a critical and selective role for HIF-2α in persistence of neutrophilic inflammation and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases.

    Research areas

  • AGING NEUTROPHILS, IN-VITRO, INFLAMMATION, APOPTOSIS, HIF-1-ALPHA, HIF, LIPOPOLYSACCHARIDE, MACROPHAGES, RESOLUTION, GENE

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