Monocytes should be considered to be in transport from their site of origin to the site of function, i.e. the tissues and body cavities. In the tissues, monocytes differentiate first into exudate macrophages, which still have many characteristics of monocytes, and then into resident macrophages. It is not known what functions monocytes exert when they reside in the circulation. The following summary concerns the functional abilities of monocytes and monocyte-
derived (exudate) macrophages when these cells are studied in vitro.
Monocytes arc well equipped to ingest opsonized microorganisms, red blood cells and other materials. The process of phagocytosis can be divided into a series of stages. First, the (opsonized) particles attach to the surface of the phagocyte. The opsonins serve-as ligands for the binding of the particles to specific receptors on the surface of the monocytes; nonop-sonized microorganisms and other cells can also bind by sugars in their cell surface to lectin-like receptors on monocytes. After ligation of the particle to the cell surface, a signal is generated that promotes the internalization process. Pseudopods of the cell advance by assembly of actin filaments that reach the membrane and form a network in the pseudopods. The pseudopods adhere closely to the particle by-interaction of the ligand with the receptors on the cell surface. This process is called the zipper mechanism (Figure 1). When the engulfment is completed the particle resides in the cytoplasm in a vacuole, which is formed by the inverted cell membrane, and called a phagosome. Next lysosomes fuse with the phagosome and lysosomal enzymes are released into the phagosome and come in contact with the phagocytosed particle. The following step in this process is that microbicidal mechanisms and digestive processes come into operation.
The antimicrobial functions of monocytes are mediated by oxygen-dependent and oxygen-independent mechanisms. The respiratory burst that accompanies phagocytosis leads to the formation of reactive oxygen metabolites including superoxide anion (O2-) and hydrogen peroxide (H202). After fusion of the phagosome with granules that contain peroxidase, this enzyme together with H202 and a halide, such as chloride, forms HOC1, a hypohalite with microbicidal activities. In mice, but not in humans, (exudate) macrophages form nitric oxide, which may be involved in antimicrobial activities of these cells. The oxygen-independent antimicrobial mechanisms of monocytes and (exudate)
Opsonization of particle igG \
Attachment of particle to cell
Figure 1 Various stages of the phagocytosis process.
macrophages include vacuolar acidification, nutrient deprivation and the action of antimicrobial polypeptides. Monocytes and macrophages contain granule-associated polypeptides such as lysozyme, defensins (only in rabbit alveolar macrophages), serprocidins (i.e. cathepsin G, elastase, proteinase 3 and azurocidin), and histone-related murine microbicidal proteins (MUMPs). The cytosol of macrophages contains a small, cationic, antimicrobial protein, called ubiquicidin. During differentiation of monocytes into resident macrophages, the monocytes lose their peroxidase activity, which is accompanied by a decrease in antimicrobial activity. However, resident macrophages can become activated by various kinds of cytokine, for example, interferon y (IFNy) formed by CD4+ T lymphocytes and natural killer (NK) cells, and then regain microbicidal activities and acquire tumoristatic or tumoricidal characteristics.
Another important function of mononuclear phagocytes, especially of (exudate) macrophages and to a smaller degree of monocytes, is the secretion of biologically active substances. Some substances are formed and secreted constitutively and others only after activation of the cells. These secretory products can be divided into enzymes (e.g. elastase, col-lagenase, proteoglycan degrading enzyme, plasminogen activator, lysosomal acid hydrolases, angioten-sin-converting enzyme, arginase), enzyme inhibitors (e.g. a2-macroglobulin, plasminogen activator inhibitor, aj-antitrypsin), arachidonic acid derivates (e.g. prostaglandins, thromboxane), plasma proteins (e.g. complement components, coagulation factors, fib-ronectin, apoprotein E), and many cytokines regulating functions or growth of other cells (e.g. IL-1, IL-6, IL-8, IL-10 and IL-12, tumor necrosis factor a (TNFct), GM-CSF, angiogenesis factor, IFNy). The repertoire of secretory products may depend on the degree of maturation and/or the state of activation of the cell, and/or its localization in the body. The existence of subsets of monocytes and macrophages that are specialized to form only one or a small number of secretory products is rather unlikely.
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