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

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, David H Dockrell, Edwin R Chilvers, Peter A Robbins, Melanie J Percy, M Celeste SimonRandall S Johnson, Stephen A Renshaw, Moira K B Whyte, Sarah R Walmsley

Research output: Contribution to journalArticlepeer-review

114 Citations (Scopus)

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.

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

Keywords

  • Animals
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Hypoxia
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Humans
  • Immunohistochemistry
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • Muramidase
  • Neutrophils
  • Phagocytosis
  • Phenotype
  • RNA
  • Respiratory Burst
  • Zebrafish

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