After being arrested on the endothelial surface, leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions. This extravasation of leukocytes, called transmigration, occurs mainly in post-capillary venules, the site at which there is maximal retraction of endothelial cells. Further movement of leukocytes is driven by chemokines produced in extravascular tissues, which stimulate leukocytes to travel along a chemical gradient (described shortly). In addition, platelet endothelial cell adhesion molecule-1 (PECAM-1) (also called CD31), an adhesion molecule of the immunoglobulin (Ig) superfamily expressed on leukocytes and endothelial cells, mediates the binding events needed for leukocytes to traverse the endothelium. After traversing the endothelium, leukocytes pierce the basement membrane, probably by secreting collagenases, and they enter the extravascular tissue. Typically, the vessel wall is not injured during leukocyte transmigration.
Chemotaxis of Leukocytes
After exiting the circulation, leukocytes move in the tissues toward the site of injury by a process called chemotaxis, which is defined as locomotion along a chemical gradient. Both exogenous and endogenous substances can act as chemoattractants, including the following:
Bacterial products, particularly peptides with Nformylmethionine termini
Cytokines, especially those of the chemokine family
Components of the complement system, particularly C5a
Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4)
These chemoattractants are produced by microbes and by host cells in response to infections and tissue damage and during immunologic reactions. All act by binding to seventransmembrane G protein-coupled receptors on the surface of leukocytes. Signals initiated from these receptors activate second messengers that induce polymerization of actin, resulting in increased amounts at the leading edge of the cell and localization of myosin filaments at the back. The leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension, much like the front wheels pull an automobile with front-wheel drive. The net result is that leukocytes migrate toward the inflammatory stimulus in the direction of the locally produced chemoattractants.
The nature of the leukocyte infiltrate varies with the age of the inflammatory response and the type of stimulus. In most forms of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are gradually replaced by monocyte-derived macro phagesover24to48hours(Fig.3.5 ).Thereareseveralreasons for the early preponderance of neutrophils: they are more numerous in the blood than other leukocytes, they respond more rapidly to chemokines, and they may attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as P-and E-selectins. After entering tissues, neutrophils are short-lived; they undergo apoptosis and disappear within 24 to 48 hours. Macrophages not only survive longer but also may proliferate in the tissues, and thus they become the dominant population in prolonged inflammatory reactions. There are, however, exceptions to this stereotypic pattern of cellular infiltration. In certain infections—for example, those produced by Pseudomonas bacteria—the cellular infiltrate is dominated by neutrophils for several days; in viral infections, lymphocytes may be the first cells to arrive; some hypersensitivity reactions are dominated by activated lymphocytes, macrophages, and plasma cells (reflecting the immune response); and in allergic reactions, eosinophils may be a prominent cell type.