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Published online before print September 30, 2004

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(Journal of Leukocyte Biology. 2005;77:33-43.)
© 2005 by Society for Leukocyte Biology

ANCA induces ß₂ integrin and CXC chemokine-dependent neutrophil-endothelial cell interactions that mimic those of highly cytokine-activated endothelium

Division of Medical Sciences, The School of Medicine, University of Birmingham, Edgbaston, United Kingdom

¹ Correspondence: Renal Immunobiology, Division of Medical Sciences, The School of Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: C.O.S.Savage{at}bham.ac.uk

Antineutrophil cytoplasm antibodies (ANCA) activate neutrophils to undergo a series of coordinated interactions, leading to transendothelial migration, eventually culminating in vascular destruction. The molecular events underlying neutrophil recruitment in ANCA-associated vasculitis need to be defined to enable effective therapeutic manipulation. A flow-based adhesion assay was used to investigate the role of ß₂ integrins (CD11a/CD18 and CD11b/CD18) and chemokine receptors [CXC chemokine receptor (CXCR)1 and CXCR2] in neutrophil migration through the endothelium. Two endothelial models were used: a highly activated model stimulated with 100 U/ml tumor necrosis factor (TNF-) and a minimally activated model stimulated with 2 U/ml TNF- and in which ANCA was present as a secondary neutrophil stimulus. CD11a/CD18, CD11b/CD18, and CXCR2 contributed to adhesion and transendothelial migration in both models. However, when the endothelium was minimally activated with TNF-, CD11b/CD18 played an important role in stabilizing adhesion induced by ANCA immunoglobulin G (IgG). Analysis of ß₂ integrins and chemokine receptors demonstrated that ANCA IgG had no effect on expression levels at the neutrophil surface but enabled an active conformational change of CD11b/CD18. Similar molecular mechanisms control neutrophil adhesion and migration through highly or minimally TNF--activated endothelium. However, the direct ANCA-mediated neutrophil stimulation is needed to drive migration through minimally activated endothelium, and CD11b/CD18 is recruited for greater stability of adhesion during this process and can undergo an activatory, conformational change in response to ANCA IgG.

Key Words: neutrophil • endothelium • integrins • chemokines

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