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

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-1? and prolyl hydroxylase-3. HIF-2? has both distinct and overlapping biological roles with HIF-1? and has not previously been studied in the context of neutrophil biology. We investigated the role of HIF-2? in regulating key neutrophil functions. Human and murine peripheral blood neutrophils expressed HIF-2?, 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-2?-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-2? was temporally dissociated from HIF-1? in vivo and predominated in the resolution phase of inflammation. These data support a critical and selective role for HIF-2? in persistence of neutrophilic inflammation and provide a platform to dissect the therapeutic utility of targeting HIF-2? in chronic inflammatory diseases.

SUBMITTER: Thompson AA 

PROVIDER: S-EPMC3894493 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature