Leukocyte recruitment from the blood into tissues requires adhesion of the leukocytes to the endothelial lining of postcapillary venules followed by movement of the leukocytes through the endothelium and vessel wall into the extravascular tissue. Leukocyte recruitment into tissues is a key event in inflammatory reactions. It is a multistep process in which each step is orchestrated by different types of adhesion molecules and chemokines. Studies of the interactions of leukocytes with endothelium in vitro under conditions that mimic flowing blood, and in vivo using intravital microscopy techniques, have established a sequence of events common to migration of most leukocytes into most tissues (Fig. 1). The steps in this process are the following:

• Selectin-mediated rolling of leukocytes on endothelium. Macrophages, DCs, and other cells that encounter microbes in extravascular tissues are activated to secrete cytokines, including TNF and IL-1. These cytokines stimulate endothelial cells lining postcapillary venules at the site of an infection to express E-selectin. Endothelial cells also express P-selectin in response to histamine released from microbe-activated mast cells and thrombin produced during blood coagulation, which occurs commonly in inflammatory reactions. At these sites, blood vessels dilate and blood flow slows. As a result, leukocytes, being larger than red cells, tend to move away from the central axial flow and closer to the vessel lining, a process known as margination. This allows the ligands for E- and P-selectins expressed on the microvilli of the leukocytes to bind to the selectins that have been induced on the endothelial cells. Because the interactions of selectins with their ligands are of low affinity (Kd ∼100 μm) with a fast off-rate, they are easily disrupted by the shear force of the flowing blood. As a result, the selectin–selectin ligand bonds repeatedly form and break and the leukocytes are pushed along the endothelial surface in a rolling motion. This slowing of leukocytes on the endothelium allows the next set of stimuli in the multistep process to act on the leukocytes. Selectin-dependent rolling is also an essential first step for naive lymphocyte migration into lymph nodes, but in that case, L-selectin on the lymphocytes bind to ligands on endothelial cells, as described later in this chapter.

• Chemokine-mediated increase in affinity of integrins. Chemokines displayed on endothelial cells of postcapillary venules at the infection site bind to their receptors on the rolling leukocytes. As discussed before, this results in stronger binding of leukocyte integrins to their ligands on the endothelial surface.

• Stable integrin-mediated arrest of leukocytes on endothelium. In parallel with the activation of integrins, the expression of their Ig-superfamily ligands on the endothelial cells is upregulated by inflammatory cytokines and microbial products. These ligands include VCAM-1, which binds the integrin VLA-4, and ICAM-1, which binds LFA-1 and MAC-1 integrins. Thus the leukocytes attach firmly to the endothelium, their cytoskeleton is reorganized, and they spread out on the endothelial surface.

• Transmigration of leukocytes through the endothelium. Leukocytes usually migrate out of blood vessels between endothelial cells, a process called paracellular transmigration or diapedesis, to reach extravascular tissues. Paracellular transmigration depends on interactions of integrins on the leukocytes and their ligands on the endothelial cells, as well as the contribution of other proteins, notably CD31, which is expressed on leukocytes and endothelial cells. This process requires a transient and reversible disruption of adherens junction proteins, primarily the VE-cadherin complex, that hold endothelial cells together. The mechanism responsible for disruption of the VE-cadherin complex involves activation of kinases when leukocyte integrins bind ICAM-1 or VCAM-1. The kinases phosphorylate the cytoplasmic tail of VE-cadherin, which leads to reversible disruption of the adherens complex. Less often, leukocytes have been observed to move through endothelial cells rather than between them by a poorly understood process called trans-cellular migration.

Fig1. Multistep leukocyte-endothelial interactions mediating leukocyte recruitment into tissues. (1) Production of cytokines at site of infection and tissue injury. (2) Selectin-mediated rolling of leukocytes. (3) Increase in integrin affinity. (4) Integrin-mediated firm attachment of leukocytes to endothelium. (5) Transmigration of leukocytes through endothelium. (6) Migration of leukocytes to site of infection and tis sue injury. IL-1, Interleukin-1; TNF, tumor necrosis factor.

These basic steps are seen in the migration of all leukocytes through the endothelium. However, neutrophils, monocytes, and different subsets of lymphocytes differ in which tissues they migrate into and when they do so in inflammatory reactions and the steady state. These patterns of leukocyte migration are dependent on the expression of distinct combinations of adhesion molecules and chemokine receptors, as we will discuss in more detail later.

Evidence for the essential role of selectins, integrins, and chemokines in leukocyte migration came first from antibody blockade studies and gene knockout mice and then from the discovery of rare, inherited human diseases called leukocyte adhesion deficiencies. An autosomal recessive inherited deficiency in the CD18 gene, which encodes the β subunit of LFA-1, MAC-1, and CD11cCD18, is the cause of an immune deficiency disease called type 1 leukocyte adhesion deficiency (LAD-1), in which there are marked defects in leukocyte migration and immune responses. Patients who lack the Golgi GDP-fucose transporter needed to express the carbohydrate ligands for E-selectin and P-selectin on neutrophils have similar problems, resulting in a syndrome called type 2 leukocyte adhesion deficiency (LAD-2). These disorders are characterized by recurrent bacterial and fungal infections, lack of neutrophil accumulation at sites of infection, and defects in adherence-dependent lymphocyte functions. Rare human mutations in the signaling pathways linking chemokine receptors to integrin activation also result in impaired leukocyte adhesion and recruitment into tissues and therefore ineffective leukocyte defense against infections, a syndrome called type 3 leukocyte adhesion deficiency (LAD-3).

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The Major Proinflammatory Cytokines of Innate Immunity

Migration of Naive T Cells Into Lymph Nodes

Migration of Neutrophils and Monocytes to Sites of Infection or Tissue Injury

Formation of Pus

Feedback Control of the Macrophage and Neutrophil Responses

Macrophage and Neutrophil Responses During Inflammation

Natural Killer Cells

Integrins and Integrin Ligands

Selectins and Selectin Ligands

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Phagocytosis