Recruitment of Leukocytes to Sites of Infection

Recruitment of large numbers of neutrophils, followed by monocytes, from blood into tissues typically occurs as part of the acute inflammatory response to infections and tissue injury. The cytokines TNF, IL-1, and IL-6 and che-mokines, which are secreted in the local sites of infection or tissue injury, have multiple effects on vascular endo-thelial cells, leukocytes, and bone marrow, which together increase the local delivery of cells that can fight infections and repair tissues (see Fig. 3-3, Chapter 3). Leukocyte recruitment was described in Chapter 3 and will be only briefly considered here.

Both TNF and IL-1 induce postcapillary venule endothelial cells to express E-selectin and to increase their expression of ICAM-1 and VCAM-1, the ligands for leukocyte integrins. These changes in endothelial adhesion molecule expression are the result of TNF and IL-1 activation of transcription factors, including NF-kB, leading to new adhesion molecule gene transcription. P-selectin expression is also induced on venular endothelial cells at sites of infection and tissue injury, but in large part, this is due to the effects of histamine and thrombin, which stimulate the rapid mobilization of P-selectin stored in granules in the endothelial cell to the cell surface.

TNF and IL-1 also stimulate various cells to secrete chemokines, such as CXCL1 and CCL2, that bind to receptors on neutrophils and monocytes, respectively, increase the affinity of leukocyte integrins for their ligands, and stimulate directional movement of leukocytes. The result of increased selectin, integrin, and chemokine expression is an increase in neutrophil and monocyte adhesion to endothelial cells and transmigration through the vessel wall. The leukocytes that accumulate in the tissues compose an inflammatory infiltrate. The actions of TNF on endothelium and leukocytes are critical for local inflammatory responses to microbes. If inadequate quantities of TNF are present (e.g., in patients treated with drugs that block TNF or in TNF gene knockout mice), a consequence may be failure to contain infections.

In addition, TNF, IL-1, and IL-6 produced at inflammatory sites may enter the blood and be delivered to the bone marrow, where they enhance the production of neutrophils from bone marrow progenitors, usually acting in concert with colony-stimulating factors. In this way, these cytokines increase the supply of cells that can be recruited to the sites of infection.

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