In normally flowing blood in venules, red cells are confined to a central axial column, displacing the leukocytes toward the wall of the vessel. Because blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall shear stress decreases), and more white cells assume a peripheral position along the endothelial surface. This process of leukocyte redistribution is called margination. Subsequently, leukocytes adhere transiently to the endothelium, detach and bind again, thus rolling on the vessel wall. The cells finally come to rest at some point where they adhere firmly (resembling pebbles over which a stream runs without disturbing them).

The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules on the two cell types whose expression is enhanced by cytokines. Cytokines are secreted by sentinel cells in tissues in response to microbes and other injurious agents, thus ensuring that leukocytes are recruited to the tissues where these stimuli are present.

The two major families of molecules involved in leukocyte adhesion and migration are the selectins and integrins, and their ligands. They are expressed on leukocytes and endothelial cells.

• The initial rolling interactions are mediated by a mfamily of proteins called selectins (Table 1). There are three types of selectins: one expressed on leukocytes (L-selectin), one on endothelium (E-selectin), and one in platelets and on endothelium (P-selectin). The ligands for selectins are sialylated oligosaccharides bound to mucin-like glycoprotein backbones. The expression of selectins and their ligands is regulated by cytokines produced in response to infection and injury. Tissue macrophages, mast cells, and endothelial cells that encounter microbes and dead tissues respond by secreting several cytokines, including tumor necrosis factor (TNF), IL-1, and chemokines (chemoattractant cytokines). (Cytokines are described in more detail later and in Chapter 6.) TNF and IL-1 act on the endothelial cells of postcapillary venules adjacent to the infection and induce the coordinate expression of numerous adhesion molecules. Within 1 to 2 hours the endothelial cells begin to express E-selectin and the ligands for L-selectin. Other mediators such as histamine and thrombin, described later, stimulate the redistribution of P-selectin from its normal intracellular stores in endothelial cell granules (called Weibel-Palade bodies) to the cell surface. Leukocytes express L-selectin at the tips of their microvilli and also express ligands for E- and P-selectins, all of which bind to the complementary molecules on the endothelial cells. These are low-affinity interactions with a fast offrate, and they are easily disrupted by the flowing blood. As a result, the bound leukocytes bind, detach, and bind again, and thus begin to roll along the endothelial surface.

• These weak rolling interactions slow down the leukocytes and give them the opportunity to bind more firmly to the endothelium. Firm adhesion is mediated by a family of heterodimeric leukocyte surface proteins called integrins (Table 1). TNF and IL-1 induce endothelial expression of ligands for integrins, mainly vascular cell adhesion molecule 1 (VCAM-1, the ligand for the β1 integrin VLA-4) and intercellular adhesion molecule-1 (ICAM-1, the ligand for the β2 integrins LFA-1 and Mac-1). Leukocytes normally express integrins in a lowaffinity state. Chemokines that were produced at the site of injury bind to endothelial cell proteoglycans, and are displayed at high concentrations on the endothelial surface. These chemokines bind to and activate the rolling leukocytes. One of the consequences of activation is the conversion of VLA-4 and LFA-1 integrins on the leukocytes to a high-affinity state. The combination of cytokine-induced expression of integrin ligands on the endothelium and increased integrin affinity on the leukocytes results in firm integrin-mediated binding of the leukocytes to the endothelium at the site of inflammation. The leukocytes stop rolling, their cytoskeleton is reorganized, and they spread out on the endothelial surface.

Table1. Endothelial and Leukocyte Adhesion Molecules

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