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Published online before print September 30, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0104054

Received for publication January 30, 2004.
Revised July 29, 2004.
Accepted for publication August 13, 2004.

Article

ANCA induces ₂ 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

^@ To whom correspondence should be addressed. E-mail: C.O.S.Savage{at}bham.ac.uk.

	Abstract

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 ₂ integrins (CD11a/CD18 and CD11b/CD18) and chemokines 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 ₂ integrins and chemokines 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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