Selectins Play Key Roles in Inflammation in Lymphocyte Homing

Leukocytes play important roles in many inflammatory and immunologic phenomena. The first steps in many of these phenomena are interactions between circulating leukocytes and endothelial cells prior to passage of the former out of the circulation. Work done to identify specific molecules on the surfaces of the cells involved in such interactions has revealed that leukocytes and endothelial cells contain on their surfaces specific lectins, called selectins, that participate in their intercellular adhesion. Features of the three major classes of selectins are summarized in Table 47-14. Selectins are single-chain Ca2+-binding transmembrane proteins that contain a number of domains (Figure 47-10). Their amino terminal ends contain the lectin domain, which is involved in binding to specific carbohydrate ligands.

The adhesion of neutrophils to endothelial cells of postcapillary venules can be considered to occur in four

Table 47-14. Some molecules involved in leukocyte-endothelial cell interactions.1

Molecule

Cell

L-selectin

PMN, lymphs

CD34, Gly-CAM-12 Sialyl-Lewisx and others

P-selectin

EC, platelets

P-selectin glycoprotein ligand-1 (PSGL-1) Sialyl-Lewisx and others

E-selectin

EC

Sialyl-Lewisx and others

Integrins

LFA-1

PMN, lymphs

ICAM-1, ICAM-2 (CD11a/CD18)

Mac-1

PMN

ICAM-1 and others (CD11b/CD18)

Immunoglobulin superfamily

ICAM-1

Lymphs, EC

LFA-1, Mac-1

ICAM-2

Lymphs, EC

LFA-1

PECAM-1

EC, PMN, lymphs

Various platelets

'Modified from Albelda SM, Smith CW, Ward PA: Adhesion molecules and inflammatory injury. FASEB J 1994;8:504. 2These are ligands for lymphocyte L-selectin; the ligands for neutrophil L-selectin have not been identified.

Key: PMN, polymorphonuclear leukocytes; EC, endothelial cell; lymphs, lymphocytes; CD, cluster of differentiation; ICAM, intercellular adhesion molecule; LFA-1, lymphocyte function-associated antigen-1; PEcAm-1, platelet endothelial cell adhesion cell molecule-1.

'Modified from Albelda SM, Smith CW, Ward PA: Adhesion molecules and inflammatory injury. FASEB J 1994;8:504. 2These are ligands for lymphocyte L-selectin; the ligands for neutrophil L-selectin have not been identified.

Key: PMN, polymorphonuclear leukocytes; EC, endothelial cell; lymphs, lymphocytes; CD, cluster of differentiation; ICAM, intercellular adhesion molecule; LFA-1, lymphocyte function-associated antigen-1; PEcAm-1, platelet endothelial cell adhesion cell molecule-1.

stages, as shown in Figure 47-11. The initial baseline stage is succeeded by slowing or rolling of the neu-trophils, mediated by selectins. Interactions between L-selectin on the neutrophil surface and CD34 and GlyCAM-1 or other glycoproteins on the endothelial surface are involved. These particular interactions are initially short-lived, and the overall binding is of relatively low affinity, permitting rolling. However, during

L-selectin

Lectin

Figure 47-10. Schematic diagram of the structure of human L-selectin. The extracellular portion contains an amino terminal domain homologous to C-type lectins and an adjacent epidermal growth factor-like domain. These are followed by a variable number of complement regulatory-like modules (numbered circles) and a transmembrane sequence (black diamond). A short cytoplasmic sequence (open rectangle) is at the carboxyl terminal. The structures of P- and E-selectin are similar to that shown except that they contain more complement-regulatory modules. The numbers of amino acids in L-, P-, and E- selectins, as deduced from the cDNA sequences, are 385, 789, and 589, respectively. (Reproduced, with permission, from Bevilacqua MP, Nelson RM: Selectins. J Clin Invest 1993;91:370.)

this stage, activation of the neutrophils by various chemical mediators (discussed below) occurs, resulting in a change of shape of the neutrophils and firm adhesion of these cells to the endothelium. An additional set of adhesion molecules is involved in firm adhesion, namely, LFA-1 and Mac-1 on the neutrophils and ICAM-1 and ICAM-2 on endothelial cells. LFA-1 and Mac-1 are CD11/CD18 integrins (see Chapter 52 for a discussion of integrins), whereas ICAM-1 and ICAM-2 are members of the immunoglobulin superfamily. The fourth stage is transmigration of the neutrophils across the endothelial wall. For this to occur, the neutrophils insert pseudopods into the junctions between endothe-lial cells, squeeze through these junctions, cross the basement membrane, and then are free to migrate in the extravascular space. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) has been found to be localized at the junctions of endothelial cells and thus may have a role in transmigration. A variety of biomol-ecules have been found to be involved in activation of neutrophil and endothelial cells, including tumor necrosis factor a, various interleukins, platelet activating factor (PAF), leukotriene B4, and certain complement fragments. These compounds stimulate various signaling pathways, resulting in changes in cell shape and function, and some are also chemotactic. One important functional change is recruitment of selectins to the cell surface, as in some cases selectins are stored in granules (eg, in endothelial cells and platelets).

Baseline

Baseline

Rolling

Activation and firm adhesion

Transmigration

Rolling

Activation and firm adhesion

Transmigration

Figure 47-11. Schematic diagram of neutrophil-endothelial cell interactions. A: Baseline conditions: Neutrophils do not adhere to the vessel wall. B: The first event is the slowing or rolling of the neutrophils within the vessel (venule) mediated by selectins. C: Activation occurs, resulting in neutrophils firmly adhering to the surfaces of endothelial cells and also assuming a flattened shape. This requires interaction of activated CD18 integrins on neutrophils with ICAM-1 on the endothelium. D: The neutrophils then migrate through the junctions of endothelial cells into the interstitial tissue; this requires involvement of PECAM-1. Chemotaxis is also involved in this latter stage. (Reproduced, with permission, from Albelda SM, Smith CW, Ward PA: Adhesion molecules and inflammatory injury. FASEB J 1994;8;504.)

The precise chemical nature of some of the ligands involved in selectin-ligand interactions has been determined. All three selectins bind sialylated and fucosy-lated oligosaccharides, and in particular all three bind sialyl-LewisX (Figure 47-12), a structure present on both glycoproteins and glycolipids. Whether this compound is the actual ligand involved in vivo is not estab-

4GlcNAc---

fa 1-3 Fuc lished. Sulfated molecules, such as the sulfatides (Chapter 14), may be ligands in certain instances. This basic knowledge is being used in attempts to synthesize compounds that block selectin-ligand interactions and thus may inhibit the inflammatory response. Approaches include administration of specific monoclonal antibodies or of chemically synthesized analogs of sialyl-LewisX, both of which bind selectins. Cancer cells often exhibit sialyl-LewisX and other selectin ligands on their surfaces. It is thought that these ligands play a role in the invasion and metastasis of cancer cells.

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