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

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

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

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