Leukocyteendothelial Interactions And Leukocyte Extravasation

Selectins, integrins, and chemokines work in concert to govern the leukocyte-endothelial interactions that are required for migration of leukocytes into tissues (Fig. 3-3). Studies of these interactions under flow conditions in vitro, and in vivo, by use of intravital microscopic techniques, have established a sequence of events common to migration of most leukocytes into most tissues. These events include the following.

• Selectin-mediated rolling of leukocytes on endothe-

lium. In response to microbes and cytokines produced by cells (e.g., macrophages) that encounter the microbes, endothelial cells lining postcapillary venules at the site of infection rapidly increase surface expression of selectins. Leukocytes move close to the endothelium-lined walls of venules in sites of innate immune responses as a result of vasodilation and slowing of blood flow, and the selectin ligands on the microvilli of the leukocytes bind to the selectins on the endothelial cells. Because selectin-selectin ligand interactions are of low affinity (Kd ~100 mm) with a fast off-rate, they are easily disrupted by the shear force of the flowing blood. As a result, the leukocytes repetitively detach and bind again and thus roll along the endothelial surface. This slowing of leukocytes on the endothelium allows the next set of stimuli in the multistep process to act on the leukocytes.

• Chemokine-mediated increase in affinity of integrins. As discussed earlier, chemokines are produced at an infection site by various cell types in response to a variety of pathogens or endogenous stimuli. Once secreted, they are transported to the luminal surface of the endothelial cells of postcapillary venules, where they are bound by heparan sulfate glycosaminoglycans and are displayed at high concentrations. At this location, the chemokines bind to specific chemokine receptors on the surface of the rolling leukocytes. Leukocyte integrins are in a low-affinity state in unacti-vated cells and ineffective in mediating adhesion interactions. Two consequences of chemokine receptor signaling are enhanced affinity of leukocyte integrins

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