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Published online before print January 30, 2007

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(Journal of Leukocyte Biology. 2007;81:1236-1244.)
© 2007 by Society for Leukocyte Biology

Ascorbate deficiency results in impaired neutrophil apoptosis and clearance and is associated with up-regulation of hypoxia-inducible factor 1

Free Radical Research Group, Pathology Department, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand

¹ Correspondence: Free Radical Research Group, Pathology Dept., Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch, New Zealand. E-mail: margret.vissers{at}chmeds.ac.nz

Some cells, including neutrophils, accumulate high intracellular ascorbate concentrations, which suggests that they have an important function in these cells. In this study we have used L-gulono--lactone oxidase (Gulo)–/– mice, which are unable to synthesize ascorbate, to generate ascorbate-deficient neutrophils and have used these to investigate the effect of ascorbate on neutrophil function. Peritoneal neutrophils from ascorbate-deficient animals had normal morphology and respiratory burst activity but failed to undergo spontaneous apoptosis, determined by morphology and the surface expression of phosphatidylserine. Initially, there was increased cell survival, but death eventually occurred by necrosis within 48 h. Neutrophils persisted in thioglycollate-induced inflammation in Gulo–/– mice with the later appearance of necrotic cells, suggesting that apoptosis was also affected in vivo. Also, ascorbate-deficient neutrophils were not recognized by macrophages in an in vitro assay for phagocytosis, providing further evidence for defective apoptosis and clearance. Neutrophils from Gulo–/– mice had elevated levels of hypoxia-inducible factor (HIF)-1, a transcription factor regulated by Fe²⁺-dependent hydroxylases which require ascorbate for optimal activity. HIF-1 has been shown previously to inhibit neutrophil apoptosis under hypoxic conditions. Our results suggest that in ascorbate deficiency, up-regulation of HIF-1 blocks neutrophil apoptosis under normoxic conditions and that this represents a novel and important function for vitamin C in inflammatory cells.

Key Words: vitamin C • neutrophil necrosis • HIF hydroxylases • neutrophil clearance

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