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

Abstract

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.

Anti-inflammatory effects of a methanol extract from Pulsatilla koreana in lipopolysaccharide-exposed rats

“…PGE2 is implicated in inducing the production of various chemoattractants and pro-inflammatory cytokines (30). Intracellular adhesion molecule-1 (ICAM-1) is a cell surface protein expressed on the vascular endothelium, which is important in the adhesion of leukocytes to activated endothelium (31). The cytokine-induced neutrophil chemoattractant-1 (CINC-1) is a rat homolog for the human interleukin (IL)-8 (32), which is one of the most potent mediators that recruit neutrophils to the site of injury.…”

The Functional Interaction of the β2 Integrin Lymphocyte Function-Associated Antigen-1 with Junctional Adhesion Molecule-A Is Mediated by the I Domain

“…Homophilic JAM-A interactions between leukocytes and the endothelium may contribute to transmigration in addition to heterophilic interaction of JAM-A with its integrin receptor LFA-1 (3), possibly by a molecular zipper-like mechanism (27). To address the issue of whether JAM-A-LFA-1 interactions also occur in leukocytes other than lymphocytes, we have now performed adhesion assays using monocytic cells on purified JAM-A.Fc.…”

Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes

“…The transmigration of IS-CD8 þ cells from the bloodstream through the pancreatic endothelium and into the islets is essential for the destruction of b cells. The specific molecular mechanisms governing these processes are not, as yet, completely understood (2). The transendothelial migration of T cells consists of the following basic steps: initial adhesion followed by tethering and rolling, arrest of rolling resulting in firm adhesion, and extravasation followed by migration through the endothelial cell barrier (3).…”