| First Author | Hahm E | Year | 2013 |
| Journal | Blood | Volume | 121 |
| Issue | 19 | Pages | 3789-800, S1-15 |
| PubMed ID | 23460613 | Mgi Jnum | J:197556 |
| Mgi Id | MGI:5493367 | Doi | 10.1182/blood-2012-11-467985 |
| Citation | Hahm E, et al. (2013) Extracellular protein disulfide isomerase regulates ligand-binding activity of alphaMbeta2 integrin and neutrophil recruitment during vascular inflammation. Blood 121(19):3789-800, S1-15 |
| abstractText | beta2 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 alphaLbeta2 or alphaMbeta2 null mice suggest that extracellular PDI regulates alphaMbeta2 integrin-mediated adhesive function of neutrophils during vascular inflammation. Consistently, we show that neutrophil surface PDI is important for alphaMbeta2 integrin-mediated adhesion of human neutrophils under shear and static conditions and for binding of soluble fibrinogen to activated alphaMbeta2 integrin. Confocal microscopy and biochemical studies reveal that neutrophil surface PDI interacts with alphaMbeta2 integrin in lipid rafts of stimulated neutrophils and regulates alphaMbeta2 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. |
