Conclusions

During the past 5 years, it has been established that new receptors such as JAMs and their integrin counterreceptors play major roles in leukocyte transmigration. Also, the fate of VE-cadherin during leukocyte transmigration is now better understood. In particular, it has been shown that membrane-bound neutrophil elastase and cathepsin G facilitate neutrophil transmigration by cleaving the extracellular part of VE-cadherin.

These adhesive receptors are definitely more than just a molecular glue, because it is suspected that they mediate intracellular signaling. Thus, some data from our laboratory suggest the existence of VE-cadherin-mediated signaling pathways triggered by the destabilization of cadherin junctions. This pathway leads eventually to the restoration of endothelium integrity by a neosynthesis of VE-cadherin molecules. The molecules involved in this pathway remain to be determined. Nevertheless, several elements suggest that b-catenin and possibly the Wnt signaling pathway might play a role in the restoration of endothelium integrity.

Abetter understanding of the sequential events occurring during transendothelial migration of leukocytes may lead to the discovery of new classes of target molecules for the design of novel drugs that are able to interfere with the transmigration process. Such drugs could have major applications in several important human illnesses such as polyarthritis or cancer.

Glossary

Endothelium: Monolayer of endothelial cells that line the inside of vascular tree.

Neutrophils: A subtype of white cells.

Transmigration: Cellular process allowing white cells to migrate across the endothelial barrier.

VE cadherin: Ca++-dependent adhesive receptor exclusively expressed in endothelium.

References

1. Worthylake, R. A., and Burridge, K. (2001). Leukocyte transendothelial migration orchestrating the underlying molecular machinery. Curr. Opin. Cell Biol. 13, 569-577.

2. Owen, C. A., Campbell, M. A., Sannes, P. L., Boukedes, S. S., and Campbell, E. J. (1995). Cell surface-bound elastase and cathepsin G on human neutrophils: A novel, non-oxidative mechanism by which neu-trophils focus and preserve catalytic activity of serine proteinases. J. Cell. Biol. 131, 775-789. This paper describes the translocation of serine proteases such as elastase and cathepsin G from azurophil granules to the cell surface after stimulation of neutrophils by chemokines. These cell surface—bound proteases are catalytically active and resistant to proteinase inhibitors.

3. Newman, P. J. (1997). The biology of PECAM-1. J. Clin. Invest. 99, 3-8.

4. Bibert, S., Jaquinod, M., Concord, E., Ebel, C., Hewat, E., Vanbelle, C., Legrand, P., Weidenhaupt, M., Vernet, T., and Gulino-Debrac, D. (2002). Synergy between extracellular modules of vascular endothelial cadherin promotes homotypic hexameric interactions. J. Biol. Chem. 277, 12790-12801.

5. Muller, W. A. (2003). Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 24, 327-334.

6. Weber, C. (2003). Novel mechanistic concepts for the control of leukocyte transmigration: Specialization of integrins, chemokines, and junctional molecules. J. Mol. Med. 81, 4-19.

7. Schenkel, A. R., Mamdouh, Z., Chen, X., Liebman, R. M., and Muller, W. A. (2002). CD99 plays a major role in the migration of monocytes through endothelial junctions. Nat. Immunol. 143-150.

8. Shaw, S. K., Bamba, P. S., Perkins, B. N., and Luscinskas, F. W. (2001). Real-time imaging of vascular endothelial-cadherin during leukocyte transmigration across endothelium. J. Immunol. 167, 23232330. Using a VE-cadherin/green fluorescent protein fusion construct (VEcadGFP), Shaw et al. visualized alterations in endothelial junc-tional structures in real time during transmigration of human neu-trophils and monocytes in an in vitro flow model. They show that migrating leukocytes appeared to push aside VEcadGFP in the plane of the junction, and this displaced material subsequently diffused back to refill the junction.

9. Cepinskas, G., Sandig, M., and Kvietys, P. R. (1999). PAF-induced elastase-dependent neutrophil transendothelial migration is associated with the mobilization of elastase to the neutrophil surface and localization to the migrating front. J. Cell Sci. 112, 1937-1945.

10. Hermant, B., Bibert, S., Concord, E., Dublet, B., Weidenhaupt, M., Vernet, T., and Gulino-Debrac D. (2003). Identification of proteases involved in the proteolysis of VE cadherin during neutrophil transmigration. J Biol Chem 278, 14002-14012. This paper established that neutrophil elastase and cathepsin G, bound at the surface of transmigrating neutrophils, are able to cleave VE-cadherin at endothelial cell—cell junctions, thus facilitating neutrophil diapedesis.

Capsule Biography

Dr. Gulino-Debrac is a senior scientist from the Centre National de la Recherche Scientifique (CNRS). Since 1996 she has been in charge of a group working on VE-cadherin in Institut de Biologie Structurale JeanPierre Ebel (Grenoble, France). Her work is supported by grants from the CNRS, the Commissariat à l'Energie Atomique (CEA), and the Ligue contre le Cancer.

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