Novel mechanistic concepts for the control of leukocyte transmigration: specialization of integrins, chemokines, and junctional molecules

The emigration of leukocytes from the circulation is a critical step during immune surveillance and inflammatory reactions and is governed by a coordinated interplay involving a spectrum of adhesion and signal molecules. As the original multistep model of leukocyte trafficking undergoes continuous revision and refinement, the identification of additional molecules and the emergence of novel concepts for their intricately overlapping functions indicate that this process is still not completely understood. Early studies defining the multistep model described the rapid transition of selectin-mediated leukocyte rolling into integrin-dependent arrest followed by transendothelial diapedesis. It has become apparent that highly specialized chemoattractive cytokines termed chemokines and their heptahelical receptors are involved in the emigration of leukocytes not only by inducing chemotaxis but also by regulating integrins to trigger cell arrest in shear flow. In light of the enormously pleiotropic role of integrins and chemokines in vertebrate biology, this review summarizes and highlights selected aspects of currently evolving concepts refining the multistep model: (a) the differential activation of integrin avidity by chemokines and its implications, (b) the functional specialization of chemokines and their receptors in leukocyte recruitment, and (c) the multilayered molecular zipper controlling the completion of diapedesis at interendothelial junctions.