title: Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model.
abstract: The oxygen-sensing transcription factor hypoxia-inducible factor-1α (HIF-1α) plays a critical role in the regulation of myeloid cell function. The mechanisms of regulation are not well understood, nor are the phenotypic consequences of HIF modulation in the context of neutrophilic inflammation. Species conservation across higher metazoans enables the use of the genetically tractable and transparent zebrafish (Danio rerio) embryo to study in vivo resolution of the inflammatory response. Using both a pharmacologic approach known to lead to stabilization of HIF-1α, and selective genetic manipulation of zebrafish HIF-1α homologs, we sought to determine the roles of HIF-1α in inflammation resolution. Both approaches reveal that activated Hif-1α delays resolution of inflammation after tail transection in zebrafish larvae. This delay can be replicated by neutrophil-specific Hif activation and is a consequence of both reduced neutrophil apoptosis and increased retention of neutrophils at the site of tissue injury. Hif-activated neutrophils continue to patrol the injury site during the resolution phase, when neutrophils would normally migrate away. Site-directed mutagenesis of Hif in vivo reveals that hydroxylation of Hif-1α by prolyl hydroxylases critically regulates the Hif pathway in zebrafish neutrophils. Our data demonstrate that Hif-1α regulates neutrophil function in complex ways during inflammation resolution in vivo.
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Elks
authors.forename: Fredericus J
authors.initials: FJ
authors.lastname: van Eeden
authors.forename: Giles
authors.initials: G
authors.lastname: Dixon
authors.forename: Xingang
authors.initials: X
authors.lastname: Wang
authors.forename: Constantino Carlos
authors.initials: CC
authors.lastname: Reyes-Aldasoro
authors.forename: Philip W
authors.initials: PW
authors.lastname: Ingham
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000276:immunology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000276:immunology; D005260:Female; D014644:Genetic Variation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000276:immunology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D029961:Zebrafish Proteins; C000630526:arnt protein, zebrafish; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator