The migration of leukocytes out of blood vessels, the process known as extravasation, occurs in response to signals generated at sites of infection. Under normal conditions, leukocytes travel in the center of small blood vessels, where blood flow is fastest. Within sites of inflammation, the vessels are dilated and the consequent slower blood flow allows leukocytes to interact in large numbers with the vascular endothelium. During an inflammatory response, the induction of adhesion molecules on the endothelial cells of blood vessels within the infected tissue, as well as induced changes in the adhesion molecules expressed on leukocytes, recruits large numbers of circulating leukocytes to the site of infection. We will describe this process with regard to monocytes and neutrophils (Fig. 3.31).
Extravasation proceeds in four stages. In the first, induction of selectins induces leukocyte rolling along the endothelium. P-selectin appears on endothelial cell surfaces within a few minutes of exposure to leukotriene B4, C5a, or histamine, which is released from mast cells in response to C5a. P-selectin can also be induced by TNF-α or LPS, and both of these induce synthesis of E-selectin, which appears on the endothelial cell surface a few hours later. When the sulfated sialyl-LewisX on monocytes and neutrophils contacts these exposed P-and E-selectins, these cells adhere reversibly to the vessel wall and begin to ‘roll’ along endothelium (see Fig. 3.31, top panel), permitting stronger interactions of the next step in leukocyte migration. Neutrophils are particularly efficient at rolling along endothelium even under flow rates that prevent rolling by other cells. Such ‘shear-resistant rolling’ by neutrophils uses long extensions of plasma membrane, termed slings, that bind the endothelium and wrap around the cell as it rolls, serving to tether the cell firmly to the endothelium and to promote rapid entry to sites of infection.
The second step depends on interactions between the leukocyte integrins LFA-1 and CR3 with adhesion molecules such as ICAM-1 (which can be induced on endothelial cells by TNF-α) and ICAM-2 on endothelium (see Fig. 3.31, bottom panel). LFA-1 and CR3 normally bind their ligands only weakly, but CXCL8 (or other chemokines), bound to proteoglycans on the surface of endothelial cells, binds to specific chemokine receptors on the leukocyte and signals the cell to trigger a conformational change in LFA-1 and CR3 on the rolling leukocyte; this greatly increases the adhesive properties of the leukocyte, as discussed in Section 3-18. The cell then attaches firmly to the endothelium, and its rolling is arrested.
In the third step the leukocyte extravasates, or crosses the endothelial wall. This step also involves LFA-1 and CR3, as well as a further adhesive interaction involving an immunoglobulin-related molecule called PECAM or CD31, which is expressed both on the leukocyte and at the intercellular junctions of endothelial cells. These interactions enable the phagocyte to squeeze between the endothelial cells. It then penetrates the basement membrane with the aid of enzymes that break down the extracellular matrix proteins of the basement membrane. The movement through the basement membrane is known as diapedesis, and it enables phagocytes to enter the subendothelial tissues.
The fourth and final step in extravasation is the migration of leukocytes through the tissues under the influence of chemokines. Chemokines such as
Selectin-mediated adhesion to leukocyte sialyl-Lewisx is weak, and allows leukocytes to roll along the vascular endothelial surface