title: Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish.
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.
authors.affiliation: Department of Infection and Immunity and.
authors.forename: A A Roger
authors.initials: AA
authors.lastname: Thompson
authors.forename: Philip M
authors.initials: PM
authors.lastname: Elks
authors.forename: Helen M
authors.initials: HM
authors.lastname: Marriott
authors.forename: Suttida
authors.initials: S
authors.lastname: Eamsamarng
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Higgins
authors.forename: Amy
authors.initials: A
authors.lastname: Lewis
authors.forename: Lynne
authors.initials: L
authors.lastname: Williams
authors.forename: Selina
authors.initials: S
authors.lastname: Parmar
authors.forename: Gary
authors.initials: G
authors.lastname: Shaw
authors.forename: Emmet E
authors.initials: EE
authors.lastname: McGrath
authors.forename: Federico
authors.initials: F
authors.lastname: Formenti
authors.forename: Fredericus J
authors.initials: FJ
authors.lastname: Van Eeden
authors.forename: Vuokko L
authors.initials: VL
authors.lastname: Kinnula
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
authors.forename: David H
authors.initials: DH
authors.lastname: Dockrell
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robbins
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Percy
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D010587:Phagocytosis; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D016897:Respiratory Burst; D015027:Zebrafish; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D009113:Muramidase; D012313:RNA; D000099162:Endothelial PAS Domain-Containing Protein 1