Monocytes, Macrophages, and Their Diseases in Man

MARTiN J. CLINE, M.D. Division of Hematology-Oncology, Department of Medicine, University of California School of Medicine, Los Angeles, California, U.S.A.

Mononuclear phagocytes are a widely distributed sys pool in a ratio of 1:3, (iii) monocytes leave the blood exponen tem of cells involved in host defense functions, immu tially with a half life of 8.4 hr, (iv), the half life may be prolonged nologic reactions, disposal of unwanted organic and in in patients with monocytosis and shortened in patients with \ organic materials, and synthesis of biologically active acute infection or splenomegaly, and (v) the normal monocyte compounds such as complement components and pros turnover rate averages 7 X lOG cells pel' hour pel' kilogram of taglandins. The system includes early precursor cells in body weight. the bone marrow, blood monocytes, alveolar and peri Available data suggest that there is no significant reentry of toneal macrophages, sinusoidal lining cells in the spleen, monocytes into the bloodstream once they have left the circu and Kupffer cells in the liver. We have recently come to lation. They enter the tissues and mature to macrophages. The understand the biology of these interesting cells and the major source of mononuclear phagocytes accumulating at in diseases they produce. flammatory foci is the monocyte precursors of the bone marrow [6]. Under noninflammatory conditions tissue macrophages may also arise from endogenous replicating cell populations, as Mononuclear phagocytes constitute a cell line that includes well as from man-ow precursors [7]. monoblasts and promonocytes in the bone marrow, the mono cyte as a cell of intermediate differentiation in the blood, and METABOLISM OF MONONUCLEAR PHAGOCYTES mature macrophages in the tissues. Tissue macrophages are The metabolism and enzymatic activities of mononuclear \ heterogeneous and include free alveolar and peritoneal macro phagocytes change profoundly with cell maturation and with phages, Kupffer cells, and the macrophages of the splenic changes in cellular environment [2,8]. The principal energy sinusoids. The concept of a continuum of cells from bone source for human monocytes and for most tissue macrophages marrow precursors to the mature tissue macro phages is impor is glycolysis, even under aerobic conditions. In contrast, the tant to an understanding of the function and metabolism of metabolism of the nonphagocytic human alveolar macrophage these cells. appears to be primaril'y aerobic [2,9]. MATURATION OF MONONUCLEAR PHAGOCYTES Macrophages have an active lipid metabolism, and phospho lipid synthesis is increased during phagocytosis. The more Mononuclear phagocytes share a common progenitor cell mature cells of the series have abundant rough endoplasmic with the granulocytic series. The earliest cells of these series reticulum and a high rate of protein synthesis. Much of this are undifferentiated lymphocyte-like cells [1]. When undiffer synthetic activity is directed toward the production oflysosomal entiated monoblasts mature and form a complex Golgi appa enzymes, but other biologically active compounds, such as ratus and a definite granule population, they are identifiable complement components, are also made in these cells. and are designated promonocytes. The promonocyte has a high The many hydrolytic enzymes localized within the lysosomal I nucleus-to-cytoplasm ratio, basophilic cytoplasm, and some cell fraction [2] probably have a major role in the digestion of peroxidase activity. The cell generally shows little phagocytic phagocytized organic materials, including erythrocytes and mi- \ activity. With maturation to the monocyte level, the activity of croorganisms. Some lysosomal enzymes may also be secreted certain acid hydrolases and the phagocytic ability increase by macro phages [10]. [2,3]. The transformation from monoblast to mature macrophage Tissue macrophages (synonym: histiocytes) are later stages is associated with changes in cellular composition and m e of maturation of monocytes. They are large cells 20 to 80 !Lm in tabolism. With maturation, the number of cytoplasmic lyso diameter, with one or more large vesicular nuclei and abundant somes and mitochondria increases, and the activity levels of cytoplasmic lysosomes, numerous mitochondria, and other in associated lysosomal and mitochondrial enzymes change Cor- \ clusions. The cells move slowly, and the movement appears to respondingly. Differentiation to mature macrophages and the depend on the complex of microfllaments. Immature macro accompanying increase in specific activity of certain lysosomal phages are capable of DNA synthesis and cell division, but enzymes are dependent on intact protein synthesis. When mac ultimately immature cells give rise to mature nondividing mac rophages are cultivated in vitro under circumstances in which rophages. These macrophages may form multinucleate giant pinocytic activity is reduced, the many secondary lysosome cells, probably by the process of cell fusion. These giant cells, gradually disappear from the cytoplasm. Such influence of \ seen in chronic granulomatous reactions, are rich in lysosomes environmental factors on the cellular level oflysosomal enzymes and hyd.rolytic enzymes. seen in vitro probably reflects the situation in the intact animal in which the functional status of the macrophages is adaptable. KINETICS OF MONONUCLEAR PHAGOCYTES This phenomenon is most clearly demonstrated in macro phages The studies of Meuret, Bammert, and Hoffmann [4,5] indi "activated" by infection with an intracellular parasite, such a cate the following: (i) normally blood monocyte counts oscillate Mycobacterium tuberculosis. These mononuclear phagocyte with a cycle frequency of 3 to 6 days, (ii) the total blood are larger, spread more readily on a sUlface, and have increased \ monocyte pool comprises a circulating pool and a marginated metabolic and microbicidal activity. Activation is thought to be mediated by products of sensitized lymphoid cells [11]. \ Supported by USPHS Grant CA 15688. Dr. Cline is a recipient of an endowment from the Ambrose and Gladys Bowyer Foundation. FUNCTIONS OF MONONUCLEAR PHAGOCYTES Reprint requests to: Martin J. Cline, M.D., Division of Hematology Oncology, Department of Medicine, University of California School of Five major areas of mononuclear phagocyte function have Medicine, Los Angeles, California 90024. been identified: (i) defense against microorganisms, (ii) removal Abbreviation: of dead or damaged cells, cell debris, and inorganic material , \ eSA: colony stimulating activity (iii) cooperative and effector functions in immune responses, \ 56 July 1978 MONOCYTES, MACROPHAGES, AND THEIR DISEASES IN MAN 57

(iv) regulatory interactions in hematopoiesis, and (v) synthesis proliferative response to mitogen and the generation of helper of other biologically active compounds, such as complement T cells requires interaction with macro phages [20]. Macrophage components and prostaglandins. These cells may also play a interactions with T cells are complex and require cells that are role in wound repair and remodeling of embr~'onic tissues. genetically compatible. In summary, it is apparent that lymphoid cells may activate DEFENSE AGAINST MICROORGANISMS macrophages and that macrophages may activate and direct Monocytes and macrophages have an important role in the lymphocytes. defense against a variety of infectious organisms [2,8,12]. They are the principal cells involved in killing intracellulaj' parasites CELL-MEDIATED CYTOTOXICITY AND ANTITUMOR such as Mycobacteria, Listeria, and Toxoplasma [13]. Macro IMMUNITY phages participating with immunocompetent cells may also kill virus and virus-infected cells, and have been demonstrated to The role of monocytes and macrophages in the control of produce interferon and to enhance lymphocyte production of neoplasia is of considerable interest but is still uncertain [21]. interferon. It is thought that mononuclear phagocytes may act as effector Mononuclear phagocytes are chemotactically attracted to an cells in various cytotoxic reactions. One form is referred to as infective focus, where they phagocytize the invading organism. antibody-dependent, cell-mediated cytotoxicity (ADCC). This The activated fifth component of complement, as well as factors mechanism depends on the coating of target cells with specific released by mitogen- and antigen-stimulated lymphocytes are antibody and subsequent identification and destruction by ef chemotactic for monocytes. fector cells. Mononuclear phagocytes, as well as granulocytes, Macrophages may accumulate at an infective focus under the can function in ADCC [22]. Macrophage recognition of anti influence of another lymphocyte-derived factor, migration-in body-coated target cells depends on membrane receptors for hibiting factor. This factor may be the same molecule that the Fc portion of subclasses of IgG antibody. activates macrophages (macrophage-activating factor) and is Monocytes and macrophages also participate in cytotoxic probably one of the inducers of the complex series of metabolic reactions mediated by humoral antibody (cytophilic antibody) changes that result in the "activated" state [14]. that attaches first to the effector cells. This type of antitumor The precise mechanisms by which mononuclear phagocytes cell activity is specific, is mediated by humoral antibody, and is kill ingested microorganisms have not been clearly defined, but effective in initiating macrophage cytotoxicity against neoplas they probably involve both oxygen-dependent and -indepen tic cells [23]. A third form of macrophage tumoricidal mecha dent cell functions [15]. Activated macrophages have been nisms is mediated by a nonimmunoglobulin humoral factor shown to kill some microorganisms more efficiently than non derived from immune lymphocytes. This material, referred to activated cells. Monocytes from patients with chronic granu as specific macrophage-activating factor, apperu's to act in a lomatous disease (CGD) manifest defective bactericidal and manner similru' to that of cytophilic antibody [23]. fungicidal capacities. Since the defect in CGD is related to Nonspecifically activated macrophages can also kill syngeneic impaired H 20 2 and O2- generation, it is likely that mononuclear tumor cells [24], a phenomenon that has been demonstrated phagocytes share this microbicidal mechanism with granulo both in vitro and in vivo. Nonspecific macrophage activation cytes [15]. occurs with intracellular parasitosis, such as Toxoplasma or tuberculosis infection, and in response to certain other biologi REMOVAL OF DAMAGED CELLS AND INORGANIC cal materials such as phytohemagglutinin, endotoxin, pyran MATERIALS copolymer, and glucan. Nonspecific activation may be mediated by a vru'iety of lymphocyte products (lymphokines) [14]. Mononuclear phagocytes remove damaged or dying cells. Activated cells ru'e larger, spread more on glass, and have a Macrophages seem able to recognize alterations in the eryth greater number of lysosomal particles than unactivated cells. rocyte surface caused by antibody, physical or chemical injUl'Y, Certain of their enzyme activities are decreased; others ru'e or aging. Splenic macrophages remove nuclear remnants and increased. They are better killer cells. precipitated hemoglobin from circulating erythrocytes ("pit The mechanisms by which activated macrophages kill tumor ting"). They also ingest immunologically injUl'ed leukocytes cells are not well understood. Killing requires intact energy and platelets. Alveolar macrophages have a special function in production but is independent of DNA, RNA, or protein syn clearing particulate material from inspired air [7). thesis. Cytotoxicity does not depend on phagocytosis, but close Macrophages also localize various inorganic materials within cell-to-cell contact is necessru-y. Transfer of lysosomal material tissues. Beryllium, zirconium, and silica cause granulomatous may be important in the killing process [25], and we have tissue reactions, and silica is known to be highly toxic to recently demonstrated that in at least some tumor model sys macrophages. tems the killing process is oxygen-independent [26]. COOPERA TIVE FUNCTIONS IN IMMUNE RESPONSES CONTROL OF GRANULOPOIESIS Mononuclear phagocytes play an important role in both cell mediated and humoral immunity [11,16]. They operate both in Monocytes and macrophages may have a regulatory role in the afferent limb of the immune response in antigen processing granulopoiesis related to their elaboration of a humoral factor. and in the efferent limb as effector cells. Monocytes and mac The formation of granulocyte and monocyte colonies in semi rophages collect, catabolize, and eliminate certain potentially solid gel cultUl'e is dependent on the presence of stimulating immunogenic materials and retain other immunogenic mole substances collectively called colony-stimulating activity (CSA) cules. Mononuclear phagocytes then can selectively present [27]. Although there is considerable biochemical heterogeneity antigen to immunocompetent T and B lymphoid cells [16]. associated with this activity, the best chru'acterized materials Antigen taken up by macrophages is partially degraded in are glycoproteins. In man, the main sources of CSA apperu' to phagolysosomes, but a small fraction may be retained in its be circulating monocytes and tissue macrophages [28,29]. native state for long periods of time [16]. Close contact between Mononuclear phagocytes may thus regulate the production of mononuclear phagocytes and lymphocytes is apparently impor granulocytes, as well as their own production. Monocyte CSA tant in the transfer of immunologic information and initiation elaboration can be increased by endotoxin and certain nucleo of the immune response [2,17-19]. tides. Macrophages and subclasses of T lymphocytes must interact The role of monocytes and macrophages in the regulation of with certain types of antigen before a maximal B lymphocyte granulopoiesis is still uncertain and will become clearer when response can be expressed. Similarly, optimal T lyml?hocyte the physiological importance of CSA has been better defined. 58 CLINE Vol. 71, No.1

MONONUCLEAR PHAGOCYTE DYSFUNCTION microbicidal activity, and (iii) malignant transformation of SYNDROMES mononuclear phagocytes. Alt hough granulocyte functional disorders have been well REFERENCES described, relatively little is known about functional diseases of 1. Bradley TR, Metcalf D: The growth of mouse bone marrow cells in vitro. Aust J Exp Bioi Med Sci 44:237-299, 1966 monocytes and macrophages. Defects in monocyte chemotaxis 2. Cline MJ: The White Cell. Cambridge, Harvard University Press, are reported in some patients with cancer and in patients and 1975 animals with Chediak-Higashi syndrome. Monocyte accumu 3. Nichols BA, Bainton DF: Differentiation of human monocytes in lation in skin windows is impaired by corticosteroids in man. bone marrow and blood. Sequential formation of two granule populations. Lab Invest 29:27-40, 1973 Monocytes from patients with chronic granulomatous disease 4. 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