Submitted November 7, 2008
Accepted February 1, 2009
Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A and PECAM-1
Abigail Woodfin, Mathieu-Benoit Voisin, Beat A. Imhof, Elisabetta Dejana, Britta Engelhardt, and Sussan Nourshargh*
Barts and the London School of Medicine and Dentistry, Queen Mary University of London, William Harvey Research Institute, London, United Kingdom
Centre Medical Universitaire, Geneva, Switzerland
FIRC Institute of Molecular Oncology and Department of Biomolecular Sciences and Biotechnologies, School of Sciences, Milan University, Milan, Italy
Theodor Kocher Institute, University of Bern, Bern, Switzerland
* Corresponding author; email: s.nourshargh{at}qmul.ac.uk.
Leukocyte transmigration is mediated by a number of endothelial cell junctional molecules but many aspects of this response remain unclear. Here we address the mechanism by which ICAM-2, JAM-A and PECAM-1 mediate neutrophil transmigration in a stimulus-dependent manner (eg mediate transmigration induced by IL-1
but not TNF
) and demonstrate their ability to act in sequence in supporting neutrophil transmigration in vivo. Using a cell transfer technique, transmigration responses of wild-type (WT) and TNF p55/p75 receptor deficient leukocytes (TNFR-/-) through mouse cremasteric venules were quantified by fluorescence intravital microscopy. Whilst WT leukocytes showed a normal transmigration response to TNF in ICAM-2-/-, JAM-A-/- and PECAM-1-/- recipient mice, TNFR-/- leukocytes exhibited a significantly reduced transmigration response in these animals. Hence, when the ability of TNF to directly stimulate neutrophils is blocked, TNF-induced neutrophil transmigration is rendered dependent on ICAM-2, JAM-A and PECAM-1 suggesting that the stimulus-dependent role of these molecules is governed by the target cell being activated. Furthermore, analysis of the site of arrest of neutrophils in inflamed tissues from ICAM-2-/-, JAM-A-/- and PECAM-1-/- mice demonstrated that these molecules act sequentially to mediate transmigration. Collectively, the findings provide novel insights into the mechanisms of action of key molecules implicated in leukocyte transmigration.
