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

TY - JOUR

T1 - Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish

AU - Thompson, A A Roger

AU - Elks, Philip M

AU - Marriott, Helen M

AU - Eamsamarng, Suttida

AU - Higgins, Kathryn R

AU - Lewis, Amy

AU - Williams, Lynne

AU - Parmar, Selina

AU - Shaw, Gary

AU - McGrath, Emmet E

AU - Formenti, Federico

AU - Van Eeden, Fredericus J

AU - Kinnula, Vuokko L

AU - Pugh, Christopher W

AU - Sabroe, Ian

AU - Dockrell, David H

AU - Chilvers, Edwin R

AU - Robbins, Peter A

AU - Percy, Melanie J

AU - Simon, M Celeste

AU - Johnson, Randall S

AU - Renshaw, Stephen A

AU - Whyte, Moira K B

AU - Walmsley, Sarah R

PY - 2014/1/16

Y1 - 2014/1/16

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Cell Hypoxia

KW - Gene Expression Regulation

KW - Green Fluorescent Proteins

KW - Humans

KW - Immunohistochemistry

KW - Inflammation

KW - Mice

KW - Mice, Inbred C57BL

KW - Muramidase

KW - Neutrophils

KW - Phagocytosis

KW - Phenotype

KW - RNA

KW - Respiratory Burst

KW - Zebrafish

U2 - 10.1182/blood-2013-05-500207

DO - 10.1182/blood-2013-05-500207

M3 - Article

C2 - 24196071

SN - 0006-4971

VL - 123

SP - 366

EP - 376

JO - Blood

JF - Blood

IS - 3

ER -