Adhesion Molecules and Neutrophil Migration - Adhesion Molecules - page 138

molecule (ESAM) (Muller, 2003). Indeed, JAM-A is a ligand for CD11a/CD18
(Ostermann et al. 2002), whereas JAM-C is a ligand for CD11b/CD18 (Santoso
et al. 2002). However, the underlying mechanisms by which these molecules
mediate the process of transendothelial migration are not well understood. Quite
remarkably, neutrophils can also take a transcellular route across the endothelium
and this process involves ICAM-1, PECAM-1, and caveolins (Feng et al. 1998,
Engelhardt and Wolburg 2004).
GENERAL MECHANISMS UNDERLYING NEUTROPHIL
TRANSEPITHELIAL MIGRATION
Much of our understanding with regard to the adhesive interactions that govern
neutrophil transepithelial migration are derived from studies using models of
intestinal epithelia, and the adhesion molecules involved in such migration of
neutrophils across epithelial barriers has been investigated using imposed gradients
of N-formyl-methionyl-leucyl-phenylalanine (fMLP) as a chemoattractant.
Unlike the interactions at the endothelium, selectins do not mediate neutrophil
adherence to the epithelium. Rather, the i rst step in this process is the adherence
of neutrophils to the basolateral surface involving β 2 integrins (Parkos et al.
1991). Although CD11b/CD18 has been described as a key neutrophil adhesion
molecule involved in the initial adherence to the epithelial basolateral surface,
CD18-independent mechanisms of neutrophil transepithelial migration have also
been documented (Vedder and Harlan, 1988, Blake et al. 2004). h us, it appears
that CD18 dependency, which underlies the initial event of neutrophil adhesion,
may be restricted to certain tissues (i.e., the intestine exhibits CD18 dependency,
whereas the lung does not) and may also depend on the particular neutrophil
chemoattractant encountered (see the next section) (Zemans et al. 2009). CD44,
a glycosylated membrane receptor, is another neutrophil adhesion molecule that
plays a role in neutrophil migration across epithelial monolayers whereupon
activation this molecule negatively regulates the transepithelial migration of
neutrophils (Si-Tahar et al. 2001). h e molecular mechanism involved in such
negative signaling following its activation may include modulation of outside-in
cell signaling.
Although the epithelial counter-receptor for CD11b/CD18 on the basolateral
epithelial surface has yet to be determined, other epithelial ligands for neutrophil
β 2 integrins have been recognized to play an important role in events that govern
neutrophil transepithelial migration. For instance, junctional adhesion molecules
(JAMs) serve as epithelial ligands for β 2 integrins and JAM-C, in particular,
plays an essential role in facilitating neutrophil movement across the epithelium,
where it binds to neutrophil CD11b/CD18 and mediates neutrophil adhesion
and subsequent migration. However, JAM-C is expressed at the level of the
desmosomes, thus its binding to CD11b/CD18 occurs at a site distal to the initial