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

Neutrophil (PMN) lifespan and function are regulated by hypoxia, via components of the HIF/VHL/hydroxylase pathway, including specific roles for hypoxia inducible factor-1α (HIF-1α) and prolyl hydroxylase-3 (PHD3). 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 have investigated the role of HIF-2α in regulating key PMN functions. Human and murine peripheral blood PMN expressed HIF-2α, with expression up-regulated by acute and chronic inflammatory stimuli and in disease-associated inflammatory PMN. HIF2A gain-of-function mutations resulted in a reduction in PMN 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 PMN displayed increased sensitivity to nitrosative stress induced apoptosis ex vivo and increased PMN 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.