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Published online before print August 3, 2007

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(Journal of Leukocyte Biology. 2007;82:1115-1125.)
© 2007 by Society for Leukocyte Biology

Conformational activation of CD11b without shedding of L-selectin on circulating human neutrophils

Y. Orr^*,, J. M. Taylor^*, S. Cartland^*, P. G. Bannon^,, C. Geczy and L. Kritharides^*,||,¶,1

^* Centre for Vascular Research and
Inflammatory Diseases Research Unit, School of Medical Sciences, The University of New South Wales, Kensington, NSW, Australia;
Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, NSW, Australia;
The Baird Institute for Applied Heart and Lung Surgical Research, NSW, Australia;
^|| The Heart Research Institute, NSW, Australia; and
^¶ Department of Cardiology, Concord Repatriation General Hospital, NSW, Australia

¹ Correspondence: Centre for Vascular Research, School of Medical Sciences, 4th Floor Wallace Wurth Building, The University of New South Wales, Kensington, NSW, 2052, Australia. E-mail: l.kritharides{at}unsw.edu.au

Membrane-activated complex 1 (Mac-1; CD11b/CD18) is a β₂ integrin implicated in the pathophysiology of neutrophil-mediated tissue injury whose functional capacity is determined by stimulus-induced conformational activation rather than up-regulation. Mac-1 up-regulation and conformational activation, together with shedding of L-selectin, are reported after in vitro neutrophil activation. However, their regulation on circulating human neutrophils during acute inflammation is unclear. Using flow cytometry, we investigated neutrophil expression of Mac-1, its activation-reporter neo-epitope CBRM1/5, and L-selectin during the inflammatory stimulus of cardiac surgery. A subpopulation of circulating neutrophils expressed CBRM1/5 (CBRM1/5+) under basal conditions (6.28±2.59%) and was persistently expanded (9.95±4.0%–15.2±4.2%; P<0.0001) peri-operatively, whereas total CD11b expression increased only transiently, intra-operatively. L-selectin expression was unchanged on CBRM1/5+ neutrophils, and soluble L-selectin levels decreased intra-operatively (P<0.01), indicating that L-selectin was not shed. Increased CBRM1/5 expression without L-selectin loss or CD11b up-regulation was replicated in vitro by neutrophil stimulation with IL-8, C3a, and platelet-activating factor. Heparin, a known CD11b ligand, which is administered during cardiac surgery, markedly reduced neutrophil expression of conformationally active CD11b in vivo and in vitro, identifying a potential mechanism for its anti-inflammatory properties. We conclude that conformational activation of CD11b occurs on circulating neutrophils in vivo and can occur in the absence of CD11b up-regulation and L-selectin shedding.

Key Words: inflammation • adhesion molecules • integrins • heparin

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