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Selectins and Integrins: Adhesion Molecules Involved in the Inflammatory Response

The specific (nonrandom) adhesion of cells to other cells or to extracellular matrices is a basic component of cell migration and recognition and underlies many biologic processes, including embryogenesis, tissue repair, and immune and inflammatory responses. It is, therefore, not surprising that many different genes have evolved that encode proteins with specific adhesive functions. Two families of adhesive proteins that are especially important in inflammation are the selectins and the integrins.
The selectins are a family of three closely related proteins that differ in their cellular distribution but all function in adhesion of leukocytes to endothelial cells. All selectins are single-chain transmembrane glycoproteins with an amino terminus that is related to carbohydrate-binding proteins known as C-type lectins. Like other C-type lectins, ligand binding by selectins is calcium-dependent (hence the name C-type). The binding of selectins to their ligands has a fast on rate but also has a fast off rate and is of low affinity; this property allows selectins to mediate initial attachment and subsequent rolling of leukocytes on endothelium in the face of flowing blood.
L-selectin, or CD62L, is expressed on lymphocytes and other leukocytes. It serves as a homing receptor for lymphocytes to enter lymph nodes by binding to high endothelial venules (HEVs). It also serves to bind neutrophils to cytokine-activated endothelial cells at sites of inflammation. L-selectin is located on the tips of microvillus projections of leukocytes, facilitating its interaction with ligands on endothelium. At least three endothelial cell ligands can bind L-selectin—glycan-bearing cell adhesion molecule-1 (GlyCAM-1), a secreted proteoglycan found on HEVs of lymph node; mucosal addressin cell adhesion molecule-1 (MadCAM-1), expressed on endothelial cells in gut-associated lymphoid tissues; and CD34, a proteoglycan on endothelial cells (and bone marrow cells). The protein backbones of all these ligands are modified by specific carbohydrates, which are the molecules actually recognized by the selectin.
E-selectin, or CD62E, previously known as endothelial leukocyte adhesion molecule-1 (ELAM-1), is expressed only on cytokine-activated endothelial cells, hence the designation E. E-selectin recognizes complex sialylated carbohydrate groups related to the Lewis X or Lewis A family found on various surface proteins of granulocytes, monocytes, and previously activated effector and memory T cells. E-selectin is important in the homing of effector and memory T cells to some peripheral sites of inflammation, particularly in the skin. Endothelial cell expression of E-selectin is a hallmark of acute cytokine-mediated inflammation, and antibodies to E-selectin can block leukocyte accumulation in vivo.
P-selectin (CD62P) was first identified in the secretory granules of platelets, hence the designation P. It has since been found in secretory granules of endothelial cells, called Weibel-Palade bodies. When endothelial cells or platelets are stimulated, P-selectin is translocated within minutes to the cell surface. On reaching the cell surface, P-selectin mediates binding of neutrophils, T lymphocytes, and monocytes. The complex carbohydrate ligands recognized by P-selectin appear similar to those recognized by E-selectin.
The essential physiologic roles of selectins have been reinforced by studies of gene knockout mice. L-selectin-deficient mice have small, poorly formed lymph nodes with few T cells. Mice lacking either E-selectin or P-selectin have only mild defects in leukocyte recruitment, suggesting that these two molecules are functionally redundant. Double knockout mice lacking both E-selectin and P-selectin have significantly impaired leukocyte recruitment and increased susceptibility to infections. Humans who lack one of the enzymes needed to express the carbohydrate ligands for E-selectin and P-selectin on neutrophils have similar problems, resulting in a syndrome called leukocyte adhesion deficiency-2 (LAD-2).
The integrin superfamily consists of about 30 structurally homologous proteins that promote cell-cell or cell-matrix interactions. The name of this family of proteins derives from the hypothesis that they coordinate (i.e., "integrate") signals from extracellular ligands with cytoskeleton-dependent motility, shape change, and phagocytic responses.
All integrins are heterodimeric cell surface proteins composed of two noncovalently linked polypeptide chains, α and β. The extracellular domains of the two chains bind to various ligands, including extracellular matrix glycoproteins, activated complement components, and proteins on the surfaces of other cells. Several integrins bind to Arg-Gly-Asp (RGD) sequences in the fibronectin and vitronectin molecules. The cytoplasmic domains of the integrins interact with cytoskeletal components (including vinculin, talin, actin, α-actinin, and tropomyosin).
Three integrin subfamilies were originally defined on the basis of which of three β subunits were used to form the heterodimers. More recently, five additional β chains have been identified.
The β1-containing integrins are also called VLA molecules, referring to "very late activation" molecules, because α1β1 and α2β1 were first shown to be expressed on T cells 2 to 4 weeks after repetitive stimulation in vitro. In fact, other VLA integrins are constitutively expressed on some leukocytes and rapidly induced on others. The β1 integrins are also called CD49a-hCD29, CD49a-h referring to different α chains (α1-α8) and CD29 referring to the common β1 subunit. Most of the β1 integrins are widely expressed on leukocytes and other cells and mediate attachment of cells to extracellular matrices. VLA-4 (α4β1) is expressed only on leukocytes and can mediate attachment of these cells to endothelium by interacting with vascular cell adhesion molecule-1 (VCAM-1). VLA-4 is one of the principal surface proteins that mediate homing of lymphocytes to endothelium at peripheral sites of inflammation.
The β2 integrins are also called CD11a-cCD18, or the leukocyte function-associated antigen-1 (LFA-1) family, CD11a-c referring to different α chains and CD18 to the common β2 subunit. LFA-1 (CD11aCD18) plays an important role in the adhesion of lymphocytes and other leukocytes with other cells, such as antigen-presenting cells and vascular endothelium. Other members of the family include CD11bCD18 (Mac-1 or CR3) and CD11cCD18 (p150,95 or CR4), which mediate leukocyte attachment to endothelial cells and subsequent extravasation. CD11bCD18 also functions as a fibrinogen receptor and as a complement receptor on phagocytic cells, binding particles opsonized with a by-product of complement activation called the inactivated C3b (iC3b) fragment.
The other integrins are expressed on platelets and other cell types, and bind to extracellular matrix proteins as well as proteins involved in coagulation.

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