PUBLICATION
Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish
- Authors
- Thompson, A.A., Elks, P.M., Marriott, H.M., Eamsamarng, S., Higgins, K.R., Lewis, A., Williams, L., Parmar, S., Shaw, G., McGrath, E.E., Formenti, F., Van Eeden, F.J., Kinnula, V.L., Pugh, C.W., Sabroe, I., Dockrell, D.H., Chilvers, E.R., Robbins, P.A., Percy, M.J., Simon, M.C., Johnson, R.S., Renshaw, S.A., Whyte, M.K., and Walmsley, S.R.
- ID
- ZDB-PUB-131203-31
- Date
- 2014
- Source
- Blood 123(3): 366-76 (Journal)
- Registered Authors
- Elks, Philip, Renshaw, Steve A.
- Keywords
- none
- MeSH Terms
-
- Animals
- Apoptosis
- Basic Helix-Loop-Helix Transcription Factors/metabolism*
- Cell Hypoxia
- Gene Expression Regulation*
- Green Fluorescent Proteins/metabolism
- Humans
- Immunohistochemistry
- Inflammation*
- Mice
- Mice, Inbred C57BL
- Muramidase
- Neutrophils/cytology
- Neutrophils/metabolism*
- Phagocytosis
- Phenotype
- RNA/metabolism
- Respiratory Burst
- Zebrafish
- PubMed
- 24196071 Full text @ Blood
Citation
Thompson, A.A., Elks, P.M., Marriott, H.M., Eamsamarng, S., Higgins, K.R., Lewis, A., Williams, L., Parmar, S., Shaw, G., McGrath, E.E., Formenti, F., Van Eeden, F.J., Kinnula, V.L., Pugh, C.W., Sabroe, I., Dockrell, D.H., Chilvers, E.R., Robbins, P.A., Percy, M.J., Simon, M.C., Johnson, R.S., Renshaw, S.A., Whyte, M.K., and Walmsley, S.R. (2014) Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish. Blood. 123(3):366-76.
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-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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping