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O. BARREIRO AND F. SÁNCHEZ-MADRID AN. R. ACAD. NAC. FARM

been shown that E-selectin is dephosphorylated upon endothelial cell
interaction with leukocytes, supporting its role as a signal transduction
molecule (27). In addition, P-selectin also functions as a signaling
receptor, mediating stimulation through its interaction with ligands
expressed by leukocytes (28). Finally, it has been recently reported that
another E-selectin ligand, CD44, can control rolling velocity and mediate
E-selectin-dependent redistribution of PSGL-1 and L-selectin to a major
rear pole on slowly rolling leukocytes through p38 signaling to promote
firm adhesion (29).

CHEMOKINE MODULATION OF INTEGRIN ACTIVITY

During their rolling, leukocytes are stimulated by chemokines and
integrin ligands expressed on the surface of endothelial cells. These
outside-in signals induce an important increase in the affinity and/or
avidity of leukocyte integrins (inside-out signals) that allows the shear-
resistant arrest of these cells and their firm adhesion to activated
endothelium.

Leukocytes modify their adhesive properties to be properly
adapted to every immune scenario (30). Hence, free-flowing leukocytes
maintain their integrins in non-adhesive conformation, to avoid unspecific
contacts with non-inflamed vascular walls, but upon encountering
localized inflammatory foci, a rapid in situ activation of leukocyte
integrins by endothelium-displayed activating signals takes place during
the transition of rolling to adhesion (31). Therefore, the regulation of
integrin adhesiveness is independent of their membrane expression and,
during the extravasation process, it is modulated by the chemokines
coupled to apical endothelial glycosaminoglycans (32). These
chemokines act by signaling through GPCRs and induce an array of
“inside-out” signals within fractions of seconds, leading to multiple
conformational changes of integrins with important effects on leukocyte
adhesion and morphology (33-35). Both the endothelium-immobilized
chemokines and the chemokine receptors expressed on leukocytes are
concentrated on microvilli to facilitate their interaction. The presence of
specific chemokines on different vascular beds contributes to orchestrate

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