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Originally published online as doi:10.1189/jlb.0507283 on August 7, 2007

Published online before print August 7, 2007
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(Journal of Leukocyte Biology. 2007;82:1278-1288.)
© 2007 by Society for Leukocyte Biology

CD31 delays phagocyte membrane repolarization to promote efficient binding of apoptotic cells

Elizabeth F. Vernon-Wilson*,1, Frédéric Auradé*,1, Lijun Tian{dagger}, Iain C. M. Rowe{dagger}, Michael J. Shipston{dagger}, John Savill* and Simon B. Brown*,2

* MRC Centre for Inflammation Research and
{dagger} Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom

2 Correspondence: Centre for Inflammation Research, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. E-mail: simon.brown{at}ed.ac.uk

Homophilic ligation of CD31, a member of the Ig superfamily of adhesion receptors, promotes macrophage clearance of apoptotic leukocytes by a mechanism hitherto not described. In studying CD31-dependent regulation of β1-integrin binding of fibronectin-coated LatexTM beads, we discovered a role for the voltage-gated potassium channel ether-à-go-go-related gene (ERG) as a downstream effector of CD31 signaling. ERG was identified by tandem mass spectrometry as a 140-kDa protein, which was selectively modified with biotin following the targeted delivery of a biotin-transfer reagent to CD31 using Fab fragments of an anti-CD31 mAb. Similar results were obtained with macrophages but not K562 cells, expressing a truncated cytoplasmic tail of CD31, which failed to regulate bead binding. Colocalization of CD31 with ERG was confirmed by immunofluorescence for K562 cells and macrophages. We now demonstrate that the resting membrane potential of macrophages is depolarized on contact with apoptotic cells and that CD31 inhibits the ERG current, which would otherwise function to repolarize. Sustained depolarization favored the firm binding of phagocytic targets, a prerequisite for efficient engulfment. Our results identify ERG as a downstream effector of CD31 in the regulation of integrin-dependent binding of apoptotic cells by macrophages.

Key Words: apoptosis • phagocytosis • integrins • ether-a-go-go related gene (ERG)






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