CXCL8 and CCL2 (see Section 3-17) are produced at the site of infection and bind to proteoglycans in the extracellular matrix and on endothelial cell surfaces. In this way, a matrix-associated concentration gradient of chemokines is formed on a solid surface along which the leukocyte can migrate to the focus of infection (see Fig. 3.31). CXCL8 is released by the macrophages that first encounter pathogens; it recruits neutrophils, which enter the infected tissue in large numbers in the early part of the induced response. Their influx usually peaks within the first 6 hours of an inflammatory response. Monocytes are recruited through the action of CCL2, and accumulate more slowly than neutrophils. Once in the inflamed tissue, neutrophils are able to eliminate many pathogens by phagocytosis. In an innate immune response, neutrophils use their complement receptors and the direct pattern recognition receptors discussed earlier in this chapter (see Section 3-1) to recognize and phagocytose pathogens or pathogen components directly or after opsonization with complement (see Section 2-13). In addition, as we will see in Chapter 10, neutrophils act as phagocytic effectors in humoral adaptive immunity, taking up antibody-coated microbes by means of specific receptors.
The importance of neutrophils in immune defense is dramatically illustrated by diseases or medical treatments that severely reduce neutrophil numbers. Patients suffering this affliction are said to have neutropenia, and they are highly susceptible to deadly infection with a wide range of pathogens and commensal organisms. Restoring neutrophil levels in such patients by transfusion
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Fig. 3.31 Neutrophils leave the blood and migrate to sites of infection in a multi-step process involving adhesive interactions that are regulated by macrophage-derived cytokines and chemokines. Top panel: the first step involves the reversible binding of a neutrophil to vascular endothelium through interactions between selectins induced on the endothelium and their carbohydrate ligands on the neutrophil, shown here for E-selectin and its ligand, the sialyl-LewisX moiety (s-Lex). This interaction cannot anchor the cells against the shearing force of the flow of blood, and thus they roll along the endothelium, continually making and breaking contact. Bottom panel: the binding does, however, eventually trigger stronger interactions, which result only when binding of a chemokine such as CXCL8 to its specific receptor on the neutrophil triggers the activation of the integrins LFA-1 and CR3 (Mac-1; not shown). Inflammatory cytokines such as TNF-α are also necessary to induce the expression of adhesion molecules such as ICAM-1 and ICAM-2, the ligands for these integrins, on the vascular endothelium. Tight binding between ICAM-1 and the integrins arrests the rolling and allows the neutrophil to squeeze between the endothelial cells forming the wall of the blood vessel (i.e., to extravasate). The leukocyte integrins LFA-1 and CR3 are required for extravasation and for migration toward chemoattractants. Adhesion between molecules of CD31, expressed on both the neutrophil and the junction of the endothelial cells, is also thought to contribute to extravasation. The neutrophil also needs to traverse the basement membrane; it penetrates this with the aid of a matrix metalloproteinase enzyme, MMP-9, that it expresses at the cell surface. Finally, the neutrophil migrates along a concentration gradient of chemokines (shown here as CXCL8) secreted by cells at the site of infection. The electron micrograph shows a neutrophil extravasating between endothelial cells. The blue arrow indicates the pseudopod that the neutrophil is inserting between the endothelial cells. Photograph (×5500) courtesy of I. Bird and J. Spragg.