The Journal of Experimental Medicine
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Published 2 December 2002. doi:10.1084/jem.20011794
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© Rockefeller University Press, 0022-1007/2002/12/1515/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 11, December 2, 2002 1515-1521

Brief Definitive Report

Adhesion Molecule–dependent Mechanisms Regulate the Rate of Macrophage Clearance During the Resolution of Peritoneal Inflammation

Geoffrey John Bellingan1, Ping Xu1, Helen Cooksley1, Helen Cauldwell2, Anthony Shock3, Stephen Bottoms1, Christopher Haslett2, Steven Eugene Mutsaers1 and Geoffrey John Laurent1

1 Centre for Respiratory Research, Rayne Institute, University College London, London WC1E 6JJ, United Kingdom
2 Rayne Laboratories, Edinburgh EH3 9YW, United Kingdom
3 Celltech R&D, Slough SL1 4EN, United Kingdom

Address correspondence to Geoffrey Bellingan, Centre for Respiratory Research Rayne Institute, Department of Medicine, University Street, London WC1E 6JJ, United Kingdom. Phone: +44 207-679-6972; Fax: +44 207-679-6973; E-mail: g.bellingan{at}ucl.ac.uk

Macrophage clearance is essential for the resolution of inflammation. Much is known about how monocytes enter the inflammatory site but little is known about how resultant macro-phages are cleared. We have previously demonstrated that macrophage clearance from resolving peritonitis occurs by emigration into draining lymphatics rather than local apoptosis. We now examine mechanisms for this process, in particular by evaluating the hypothesis that modulation of adhesion interactions between macrophages and cells lining the lymphatics regulates the rate of macrophage clearance. We demonstrate in vivo that macrophages adhere specifically to mesothelium overlying draining lymphatics and that their emigration rate is regulated by the state of macrophage activation. We observed that macrophage–mesothelial adhesion is Arg-Gly-Asp (RGD) sensitive and partially mediated by very late antigen (VLA)-4 and VLA-5 but not {alpha}v or ß2 integrins. Moreover, macrophage clearance into lymphatics can be blocked in vivo by RGD peptides and VLA-4 and VLA-5 but not ß2 blocking antibodies. This is the first evidence that macrophage emigration from the inflamed site is controlled and demonstrates that this is exerted through specific adhesion molecule regulation of macrophage–mesothelial interactions. It highlights the importance of adhesion molecules governing entry of cells into the lymphatic circulation, thus opening a new avenue for manipulating the resolution of inflammation.

Key Words: peritonitis • integrins • lymphatic system • cell movement • receptors-very late antigen


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