title: Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis.
abstract: Neutrophils are key mediators of the innate immune response and are required to function at sites of low oxygenation. We have shown that in hypoxia neutrophils are protected from apoptosis via a mechanism dependent on prolyl hydroxylase domain/hypoxia-inducible factor 1alpha (PHD/HIF-1alpha). This response would be predicted to involve the von Hippel Lindau protein (pVHL)-dependent ubiquitination and degradation of HIF-1alpha. Patients with VHL disease inherit a mutation in one VHL allele, which allows us to study the effects of heterozygous VHL expression in human neutrophils. Neutrophils exhibited a striking "partial hypoxic" pheno-type, with delayed rates of apoptosis and enhanced bacterial phagocytosis under normoxic conditions and preserved responses to low levels of oxygen. This provides direct evidence that the HIF-1alpha/VHL pathway regulates the innate immune response in humans. It also establishes that heterozygous VHL defects are sufficient to perturb normal responses and illustrates the potential to use this to address the role of HIF and VHL in human biology.
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cowburn
authors.forename: Menna R
authors.initials: MR
authors.lastname: Clatworthy
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Emma C
authors.initials: EC
authors.lastname: Roper
authors.forename: Vanessa
authors.initials: V
authors.lastname: Singleton
authors.forename: Patrick
authors.initials: P
authors.lastname: Maxwell
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
mesh_terms: D017209:Apoptosis; D015687:Cell Hypoxia; D018095:Germ-Line Mutation; D006801:Humans; D009504:Neutrophils / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*; D013296:Streptococcus pneumoniae / Q000502:physiology*; D006623:von Hippel-Lindau Disease / Q000235:genetics*