Journal
BLOOD
Volume 121, Issue 19, Pages 3789-3800Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-11-467985
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Funding
- National Institutes of Health [P30HL101302, R01HL109439]
- American Heart Association [SDG 5270005]
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beta 2 integrins play a crucial role during neutrophil recruitment into the site of vascular inflammation. However, it remains unknown how ligand-binding activity of the integrin is regulated. Using fluorescence intravital microscopy in mice generated by crossing protein disulfide isomerase (PDI) floxed mice with lysozyme-Cre transgenic mice, we demonstrate that neutrophil PDI is required for neutrophil adhesion and crawling during tumor necrosis factor-alpha-induced vascular inflammation in vivo. Rescue experiments show that the isomerase activity of extracellular PDI is critical for its regulatory effect on neutrophil recruitment. Studies with blocking anti-PDI antibodies and alpha L beta 2 or alpha M beta 2 null mice suggest that extracellular PDI regulates alpha M beta 2 integrin-mediated adhesive function of neutrophils during vascular inflammation. Consistently, we show that neutrophil surface PDI is important for alpha M beta 2 integrin-mediated adhesion of human neutrophils under shear and static conditions and for binding of soluble fibrinogen to activated alpha M beta 2 integrin. Confocal microscopy and biochemical studies reveal that neutrophil surface PDI interacts with alpha M beta 2 integrin in lipid rafts of stimulated neutrophils and regulates alpha M beta 2 integrin clustering, presumably by changing the redox state of the integrin. Thus, our results provide the first evidence that extracellular PDI could be a novel therapeutic target for preventing and treating inappropriate neutrophil sequestration.
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