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 publication

DOI

10.1182/blood-2013-05-500207

Type

Journal article

Journal

Blood

Publication Date

16/01/2014

Volume

123

Pages

366 - 376

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