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

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