Cell Adhesion Molecules and Leukocyte Trafficking in Sepsis

Abstract

Histologically, septic foci are characterized by a marked infiltrate of leukocytes, and in particular neutrophils. The movement of leukocytes from the circulation to such foci results from interactions between leukocytes and endothelial cells, controlled by the coordinated expression of cell adhesion molecules (CAM) on both cell types. CAM mediate attachment of cells both to one another and to extracellular matrix. They include the selectins, integrins, cadherins and the immunoglobulin superfamily (Fig. 1). Bacterial products and host pro-inflammatory mediators can initiate changes in CAM expression. CAM are, however, much more than a ‘molecular glue’ providing structural integrity to tissues and binding leukocytes. Traversing the cell membrane, CAM have intracellular domains linked to signaling proteins and cytoskeletal structures that allow functional responses in cells following binding of CAM to their ligands (so called ‘outside-in signaling’). Thus, CAM inform a cell of its position and orientation relative to other cells and matrix components. Cellular responses to ligand binding include altered expression and binding affinity of other CAM (so called ‘inside-out signaling’), increased gene expression, exocytosis, and altered structural rigidity promoting locomotion. It is through these mechanisms that specific CAM not only provide adhesive bonds, but also trigger the next stages of the highly regulated leukocyte recruitment process. The importance of CAM in modulating host defense is emphasized by congenital defects in leukocyte adhesive function that render patients more susceptible to infection [1].