Submitted April 25, 2006
Accepted June 7, 2006
Neutrophils from patients with heterozygous germline
mutations in the von Hippel Lindau protein (VHL) display
delayed apoptosis and enhanced bacterial phagocytosis
Sarah R Walmsley, Andrew S Cowburn, Menna R Clatworthy, Nicholas W Morrell, Emma C Roper, Vanessa Singleton, Patrick Maxwell, Moira KB Whyte, and Edwin R Chilvers*
Department of Medicine, University of Cambridge School of Clinical Medicine
Department of Medical Genetics, University of Cambridge
Academic Unit of Respiratory Medicine, Division of Genomic Medicine, University of Sheffield
Department of Nephrology, Hammersmith Campus, Imperial College
* Corresponding author; email: erc24{at}cam.ac.uk.
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 PHD/HIF-1
-
dependent mechanism. This response would be predicted to
involve the von Hippel Lindau protein (pVHL)- dependent
ubiquitination and degradation of HIF-1. Patients
with VHL disease inherit a mutation in one VHL allele
allowing us to study the effects of heterozygous VHL
expression in human neutrophils. Neutrophils exhibited a
striking 'partial hypoxic' phenotype, 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-1/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.
