Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis
- 15 October 2002
- journal article
- Published by American Society of Hematology in Blood
- Vol. 100 (8), 3008-3016
- https://doi.org/10.1182/blood-2002-02-0454
Abstract
Neutrophil apoptosis represents a major mechanism involved in the resolution of acute inflammation. In contrast to the effect of hypoxia observed in many other cell types, oxygen deprivation, as we have shown, causes a profound but reversible delay in the rate of constitutive apoptosis in human neutrophils when aged in vitro. This effect was mimicked by exposing cells to 2 structurally unrelated iron-chelating agents, desferrioxamine (DFO) and hydroxypyridines (CP-94), and it appeared specific for hypoxia in that no modulation of apoptosis was observed with mitochondrial electron transport inhibitors, glucose deprivation, or heat shock. The involvement of chelatable iron in the oxygen-sensing mechanism was confirmed by the abolition of the DFO and CP-94 survival effect by Fe2+ ions. Although hypoxia inducible factor-1α (HIF-1α) mRNA was identified in freshly isolated neutrophils, HIF-1α protein was only detected in neutrophils incubated under hypoxic conditions or in the presence of DFO. Moreover, studies with cyclohexamide demonstrated that the survival effect of hypoxia was fully dependent on continuing protein synthesis. These results indicate that the neutrophil has a ferroprotein oxygen-sensing mechanism identical to that for erythropoietin regulation and results in HIF-1α up-regulation and profound but reversible inhibition of neutrophil apoptosis. This finding may have important implications for the resolution of granulocytic inflammation at sites of low-oxygen tension.Keywords
This publication has 56 references indexed in Scilit:
- Neutrophil Priming: Pathophysiological Consequences and Underlying MechanismsClinical Science, 1998
- Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in vivo.American Journal of Respiratory Cell and Molecular Biology, 1995
- Resolution of acute inflammation and the role of apoptosis in the tissue fate of granulocytesClinical Science, 1992
- Macrophage recognition of senescent neutrophilsClinical Science, 1992
- Oxidative damage to synovial fluid from the inflamed rheumatoid joint detected by 1H NMR spectroscopyJournal of Pharmaceutical and Biomedical Analysis, 1991
- Neutrophil apoptosis and clearance from neonatal lungsThe Lancet, 1991
- Oxidative damage to hyaluronate and glucose in synovial fluid during exercise of the inflamed rheumatoid joint. Detection of abnormal low-molecular-mass metabolites by proton-n.m.r. spectroscopyBiochemical Journal, 1991
- Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosisNature, 1990
- The neutrophilCurrent Opinion in Immunology, 1989
- Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.JCI Insight, 1989