Development

Monocytes, the circulating precursors of tissue macrophages, develop more rapidly in the bone marrow and remain longer in the circulation than do neutrophils (see Table 121-1). The first recognizable monocyte precursor is the monoblast, followed by the promonocyte, with cytoplasmic granules and an indented nucleus, and, finally, the fully developed monocyte. A mature monocyte is larger than a neutrophil and has cytoplasm filled with granules containing hydrolytic enzymes. The transition from monoblast to mature circulating monocyte requires about 6 days. Monocytes retain a limited capacity to divide, and they undergo considerable further differentiation after entering the tissues, where they may live for weeks to many months.

Among multiple subsets of blood monocytes, 2 major ones can be identified on the basis of surface antigens: CD14++ CD16–, originally termed “classical monocytes” because they constitute 90-95% of total monocytes, and the more mature CD14+ CD16+ “proinflammatory” monocytes, which produce more proinflammatory tumor necrosis factor-α (TNF-α) and less immunosuppressive IL-10 in response to microbial stimuli. Monocytes of either subset migrate into different tissues in response to localized inflammation or, apparently, randomly in the absence of inflammation. Once in the tissues, monocytes undergo transformation into tissue macrophages with morphologic and functional properties that are characteristic for the tissue in which they reside (see Table 122-1).

Organ-specific factors influence monocyte differentiation and endow each tissue macrophage with its characteristic features. Monocytes in the liver become Kupffer cells that bridge the sinusoids separating adjacent plates of hepatocytes. Those at the lung airway surface become large ellipsoid alveolar macrophages, and those in the bone become osteoclasts. All macrophages have at least 3 major functions in common: phagocytosis, presentation of antigens to lymphocytes, and enhancement or suppression of the immune response through release of a variety of potent hormone-like factors termed cytokines. At sites of inflammation, monocytes and macrophages can fuse to form multinucleated giant cells; these cells maintain the antimicrobial functions of macrophages.

Activation

The most important step in the maturation of tissue macrophages is the conversion from a resting to a more functionally active cell, a process driven primarily by certain cytokines and microbial products. Macrophage activation is a generic term, with the functional characteristics of an activated macrophage population varying with the cytokine or other stimulus (microbial, chemical) to which the population has been exposed. Classical activation refers to a response to infection that is driven by specifically activated T-helper 1 (Th1)–type lymphocytes and natural killer cells through their release of interferon-γ (IFN-γ). TNF-α secreted by activated macrophages amplifies their activation, as does bacterial cell wall protein or endotoxin. Alternative activation is driven by T-helper 2 (Th2)–type lymphocytes through release of interleukin (IL)-4 and IL-13, cytokines that regulate antibody responses, allergy, and resistance to parasites. Alternatively activated macrophages may have particular functional advantages, such as in wound healing and immunoregulation. In the traditional context of host defense, the term activated macrophage indicates that the “classically activated” cell has an enhanced capacity to kill microorganisms or tumor cells. These macrophages are larger, with more pseudopods and pronounced ruffling of the plasma membrane, and they exhibit accelerated activity of many functions (Table 122-2). Considering the variety of macrophage activities essential to the maintenance of homeostasis, it seems likely that so-called classically and alternatively activated macrophages are examples of a continuum of physiologic functions expressed by these long-lived cells in response to the specific task at hand.