The Journal of Experimental Medicine
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Published 4 November 2002. doi:10.1084/jem.20020324
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© Rockefeller University Press, 0022-1007/2002/11/1201 $5.00
The Journal of Experimental Medicine, Volume 196, Number 9, 1201-1212

PECAM-1 (CD31) Homophilic Interaction Up-Regulates {alpha}6ß1 on Transmigrated Neutrophils In Vivo and Plays a Functional Role in the Ability of {alpha}6 Integrins to Mediate Leukocyte Migration through the Perivascular Basement Membrane

John Dangerfield1, Karen Y. Larbi1, Miao-Tzu Huang1, Ann Dewar2 and Sussan Nourshargh1

1 Cardiovascular Medicine Unit, National Heart & Lung Institute, Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 ONN, United Kingdom
2 National Heart and Lung Institute, Electron Microscopy Unit, Imperial College, Royal Brompton Hospital, London SW3 6NP, United Kingdom

Address correspondence to Dr. Sussan Nourshargh, Cardiovascular Medicine Unit, National Heart and Lung Institute, Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. Phone: 44-20-8383-1621; Fax: 44-20-8383-1640; E-mail: s.nourshargh{at}ic.ac.uk

Platelet-endothelial cell adhesion molecule (PECAM)-1 has been implicated in leukocyte migration through the perivascular basement membrane (PBM) though the mechanisms involved are unclear. The present results demonstrate that the ability of {alpha}6 integrins to mediate neutrophil migration through the PBM is PECAM-1 dependent, a response associated with PECAM-1–mediated increased expression of {alpha}6ß1 on transmigrating neutrophils in vivo. An anti-{alpha}6 integrins mAb (GoH3) inhibited (78%, P < 0.001) neutrophil migration through interleukin (IL)-1ß–stimulated cremasteric venules, primarily at the level of the PBM, as analyzed by intravital and electron microscopy. In PECAM-1–deficient mice (KO), a reduced level of neutrophil transmigration elicited by IL-1ß (4-h reaction) was observed in both the cremaster muscle (55% inhibition, P < 0.05) and in the peritoneum (57% inhibition, P < 0.01) but GoH3 had no additional inhibitory effect on these responses. FACS® analysis of neutrophils demonstrated increased expression of {alpha}6ß1 on transmigrated peritoneal neutrophils, as compared with blood neutrophils, in wild-type but not KO mice even though neutrophils from both strains of mice exhibited comparable levels of intracellular expression of {alpha}6 as observed by immunofluorescent staining and confocal microscopy. Furthermore, mice deficient in either leukocyte or endothelial cell PECAM-1, as developed by bone marrow transplantation, demonstrated a similar level of reduced neutrophil transmigration and expression of {alpha}6ß1 on transmigrated neutrophils as that detected in KO mice.

The results demonstrate a role for PECAM-1 homophilic interaction in neutrophil transmigration and increased expression of {alpha}6ß1 on the cell surface of transmigrated neutrophils in vivo, a response that could contribute to the mechanism of PECAM-1–mediated neutrophil migration through the PBM.

Key Words: inflammation • adhesion molecules • laminin • integrins • intravital microcopy


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