Molecular Basis and Pathologic Consequences of Neutrophil Adherence to Endothelium

Abstract

The recruitment of leukocytes from the blood stream to extravascular tissue is a critical event in host defense against microbial invasion and in the repair of tissue damage. Studies by intravital microscopy have established a sequence of events involved in phagocyte emigration at sites of inflammation (1). In response to extravascular stimuli such as bacterial-derived chemoattractants or endogenous lipid and peptide mediators, signals that activate both the leukocyte and the endothelial cell are generated. As a consequence of activation, one or both cell types become adhesive leading to transient adhesion of the leukocyte to the vessel wall. The combination of these initial adhesive interactions and the shear forces caused by blood flow results in leukocyte “rolling” along the vessel wall. With further stimulation some of the rolling leukocytes adhere firmly or “stick”, and then diapedese between endothelial cells to emigrate to tissue in response to chemoattractants. These adhesive interactions - rolling, sticking, and diapedesis - are mediated by cell surface molecules expressed on the leukocytes and endothelial cells (reviewed in 2 and 3). The majority of surface molecules involved in leukocyte-endothelial adherence can be placed in two categories: leukocyte integrin receptors that interact with ligands on the endothelial cell that are members of the immunoglobulin supergene family, and selectin receptors expressed on both the leukocyte and the endothelial cell that recognize specific carbohydrate counter-structures. Known integrin/immunoglobulin family interactions include: the β₁ integrin VLA-4 (CD49d/CD29) with vascular cell adhesion molecule-1 (VCAM-1, CD106); the β₂ integrins, CD11a/CD18 (LFA-1) with intercellular adhesion molecule-1 (ICAM-1, CD54) or ICAM-2 (CD102); CDI1b/CD18 (Mac-1, Mol, CR3) with ICAM-1, and α₄β₇ with MAdCAM-1. Endothelial E-selectin (CD62E, ELAM-1), endothelial P-selectin (CD62P, GMP-140, PADGEM) and leukocyte L-selectin (CD62L, LAM-1, LECAM-1) all recognize sialyl Lewis^x (SLe^x) and other sialylated, fucosylated counter-structures (reviewed in 4 and 5), although the full spectrum of carbohydrate moieties recognized by the various selectins has not been defined. The proteins that bear the carbohydrate ligands for the selectins include the vascular mucins (6) such as PSGL-1 which presents carbohydrates to P- and E-selectin (7) and CD34 (8) and MAdCAM-1 (9) on high endothelial venules which bear an as yet incompletely characterized carbohydrate moiety recognized by murine lymphocyte L-selectin.