The delicate chromatin and the bluish color of the cytoplasm in the monocyte are most helpful in differentiating these cells from metamyelocytes or band forms of neutrophils. Granules in monocytes contain peroxidase, but are much smaller than those found in neutrophils. The cells attach avidly to plastic polystyrene or glass, are motile in their adherent state, and spread and project thin processes within 1 to 3 hours.
On phase microscopy, phase-dense granules, which correspond to lysosomes, can be seen in the cytoplasm. The lysosomes are excluded from the actin-rich thin border area of cortical cytoplasm hyaloplasm. Cell motion is ameboid in nature; large, filmy, irregular pseudopods extend slowly from the delicate cytoplasm as the cell moves randomly. Electron microscopy shows that the mature monocyte contains a horseshoe-shaped nucleus, with dense, granular peripheral chromatin surrounding extensive, light-staining central nucleoplasm Fig.
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The mitochondria are spherical or elongated and are usually located in the periphery of the abundant cytoplasm. The Golgi apparatus is well developed, and small vesicles are especially numerous in this region but may be found throughout the cytoplasm. Electron micrograph of a normal human monocyte examined for peroxidase. In the nucleus n , the chromatin is more condensed than in earlier forms, is mainly peripheral in distribution, and is interrupted at the nuclear pores. The voluminous cytoplasm c contains a full complement of organelles associated with protein synthesis and export of secretory granules.
At this stage, the two kinds of granules are approximately equal in number and similar in size and shape, ranging from 90 to nm in length and from spherical or rodlike to dumbbell in shape. Microtubules mt radiate form the cell center, where a centriole can be seen adjacent to the Golgi complex G. The moderately abundant endoplasmic reticulum has a more peripheral distribution than in the promonocyte, and modest numbers of mitochondria m are present.
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Numerous pseudopodia ps extend from the cell surface. The peripheral lacunae l represent tangential section through surface irregularities. Electron micrograph of a peroxidase-negative human macrophage that developed after 14 days in liquid culture. The eccentric nucleus contains a distinct nucleolus nu and the cytoplasm is filled with many organelles i. No peroxidase can be detected at this late stage of maturation. In addition to the occasional clear vacuoles v are many inclusions, which are peroxidase-negative granules p-g.
Their content is unknown. Differentiation of macrophages from normal human bone marrow in liquid culture.
J Clin Invest ;, with permission. At the monocyte stage, peroxidase production ceases, and the RER and Golgi complex no longer contain the enzyme, but peroxidase is present in storage granules A second population of granules is produced that contain no peroxidase 58 , 59 , In normal human monocytes, peroxidase activity can be detected in the Golgi area and in the rough endoplasmic reticulum after adherence to plastic or glass for 2 to 18 hours. Patients with hereditary deficiency of neutrophil peroxidase have monocytes that lack the enzyme in their storage granules However, after adherence and in vitro culture, peroxidase activity appears as in normal monocytes, suggesting that the peroxidase stored in monocyte granules and the peroxidase that appears in the RER and Golgi after adherence are two distinct proteins The peroxidase of the RER and Golgi is inhibited by aminotriazole and sodium azide, while that of the granules is not Macrophages represent the tissue component of the mononuclear phagocyte system.
This is a very heterogenous group of cells with many different phenotypes. In general, they are thought to arise from emigrated blood monocytes, and apparently differentiate in response to local conditions and factors 1.
Their shape is irregular, and their motility comparable to that of blood monocytes. Bleblike and filiform pseudopods are seen frequently. The cytoplasm is abundant. The nucleus is egg shaped or may be indented or elongated. The cytoplasm is sky-blue and contains coarse, azure granules and vacuoles. Electron microscopy of macrophages shows a spectrum of cell types ranging from those comparable to monocytes to much larger cells with more cytoplasm and more vacuolization and granulation Fig.
Peroxidase is seen in the RER and Golgi, but in contradistinction to monocytes, is absent in the granules. Mononuclear Phagocyte Production and Kinetics. The major site of production of mononuclear phagocytes is the bone marrow. Primitive stem cells become committed to the mononuclear phagocyte lineage in a stochastic fashion, and then, under the influence of growth factors and cytokines, differentiate into monocytes.
Myeloid cell growth is controlled by different glycoprotein growth factors that can cause the development in vitro of colonies composed of granulocytes only G-CSF , macrophages only M-CSF , both granulocytes and macrophages GM-CSF , or granulocytes, macrophages, normoblasts, megakaryocytes, mast cells, and stem cells IL-3 52 , The macrophage growth factors cause both proliferation and differentiation of primitive hematopoietic cells to monoblasts, promonocytes, and mature monocytes.
They work through specific, high-affinity cell-surface receptors that initiate the cell proliferation 52 , Receptors for M-CSF are restricted to cells of the mononuclear phagocyte system and are species specific. Mouse mononuclear phagocytes bind M-CSF specifically with high affinity The receptor for the mononuclear phagocyte growth factor, M-CSF is closely related to the c-fms proto-oncogene product 70 , The transcription factor PU.
Mononuclear phagocyte development during fetal and neonatal life is dependent on M-CSF Model of the production and kinetics of the monocyte-macrophage system in humans. The marrow and blood compartments are drawn to show their relative sizes. Subsequently, several waves of labeled cells appeared, reflecting the flow into the blood of cells labeled during promonocyte proliferation in the marrow This is about twice the promonocyte generation time of 29 hours and suggests that there are, on the average, two catenated promonocyte generations in the bone marrow of normal man Fig.
Other workers have demonstrated comparable values using different techniques 51 , Similar numbers of cells are turning over through the blood as determined from blood monocyte kinetic measurements Blood monocytes are a population of recently formed young cells on their way from the bone marrow to their ultimate sites of activity in the tissues.
Therefore, monocyte production can be calculated from the turnover of blood monocytes. Blood monocyte kinetics have been evaluated in humans by in vivo and in vitro labeling of autologous blood with tritiated diisopropyl fluorophosphate 3 H-DFP , reinjecting the labeled cells, and measuring the proportion of labeled cells present at later times by autoradiographic techniques 78 , These studies have shown the marginal monocyte pool to be about 3. Blood monocytes left the vascular system in an exponential manner with a half-time of 4.
This 8. Alterations in monocyte kinetics have been measured after the acute or chronic administration of adrenal glucocorticoids to humans 81 and mice Profound monocytopenia develops promptly in both species, and its duration and degree depend on the amount, solubility, and route of steroid administration.
In man, the cellularity of induced exudates is decreased by steroid administration The mechanism of the sudden monocytopenia is not fully understood, nor is it clear whether the reduced cellularity at the site of inflammation merely reflects the monocytopenia, is the result of other steroid effects on the monocytes or the vascular wall, or is due to yet other factors.
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In septicemia, monocytopoiesis is enhanced in the marrow, and the blood monocyte turnover rate is increased in humans The peripheral half-life of blood monocytes in subjects receiving the growth factors was reduced G-CSF administration to normal people in preparation for blood stem cell harvesting caused an eightfold increase in neutrophil and monocyte counts, and a slight decrease in platelet counts The effects of recombinant growth factors on tissue macrophage numbers and function are not known.
Recent work with mouse cells has documented that blood monocytes consist generally of two subsets These cells are thought to be resident cells recruited to tissues in the absence of inflammation Tissue macrophages arise primarily from emigrated blood monocytes that differentiate into macrophages. Chimera studies in experimental animals have shown that marked donor marrow or blood monocytes radioactive label, abnormal or opposite sex chromosome marker, unique enzyme, or distinctive morphologic marker eventually are found in tissues as macrophages.
This has been shown in the case of peritoneal macrophages 86 , 87 , 88 , 89 , liver Kupffer cells 90 , 91 , 92 , alveolar macrophages 93 , 94 , 95 , 96 , osteoclasts 97 , type A synovial cells 98 , and inflammatory tissue macrophages Studies in humans after bone marrow or liver transplants from opposite sex donors have given evidence for the bone marrow or blood origin of liver Kupffer cells and alveolar macrophages Some have contended that local proliferation of tissue macrophages plays an important physiologic role in the maintenance of macrophage numbers there.
Local proliferation of tissue macrophages in physiologic conditions contributes to tissue macrophage renewal, but the precise extent of this is unknown. Studies in mice have attempted to define the kinetics of tissue macrophages. The turnover rate for peritoneal macrophages is low about 0.
There are approximately 0. Approximately half of the labeled blood monocytes migrate to the liver, where they reside as Kupffer cells. The calculated mean turnover time for lung macrophages is about 27 days. Data for other tissue mononuclear phagocytes are not available. Some alveolar macrophages are removed by the mucociliary pathway and are expectorated or swallowed , , There is evidence that interstitial lung macrophages migrate to lymph nodes via the lymphatics , , where they may die.
Macrophages from the small intestine and liver migrate to regional lymph nodes , Macrophages in granulomas epithelioid cells and multinucleated giant cells die in situ There is no good information that tissue macrophages ever re-enter the blood. However, when researchers injected fluorescent spheres into the subcutaneous tissue of mice, the spheres were phago-cytized by exuded monocytes and then migrated to draining lymph nodes, where they had characteristics of dendritic cells These data indicate that tissue macrophages can leave one tissue subcutaneous tissue and enter another lymph node , where they may differentiate into another cell type dendritic cell Characteristics and Distribution of Tissue Macrophages.
Cells of the mononuclear phagocyte system are widely distributed throughout the body Table The cells in the various tissues are quite heterogeneous, differing in numerous parameters. Because of the broad distribution and the difficulty of isolating those deeply embedded in some tissues, it has been difficult to quantitate the numbers in different compartments or the total number in the body. Interstitial cells are likely the immediate antecedents of the free alveolar macrophages , Pulmonary macrophages are essential components of the respiratory defense system, and because of their accessibility, alveolar macrophages have been studied most extensively.
Their appearance and structure depend on the age of the cell and the nature and quantity of the material that has been endocytized.
In Giemsa- or Wright-stained preparations, their cytoplasm is gray or light blue and contains numerous cytoplasmic granules. The nuclear:cytoplasmic ratio is about Nucleoli are sometimes seen.
Diversity and functions of intestinal mononuclear phagocytes
There is abundant smooth and rough endoplasmic reticulum. Some of the inclusions contain surfactant, the phospholipid synthesized by alveolar type II cells that is important in the maintenance of normal lung function. The normal alveolar macrophage removes and degrades surfactant material It does not contain hemoglobin, and only trace amounts of iron are present. However, in situations of pulmonary hemorrhage occult or overt , large quantities of hemoglobin and iron in the form of hemosiderin can be found in the cells There is little or no peroxidase activity in alveolar macrophages, but they do contain catalase.
They have receptors for the Fc fragment of IgG and complement C3b , , Ultrastructurally, the nuclei of alveolar macrophages are polymorphous and frequently have an eccentrically placed nucleus with a nucleolus Multinucleated cells are rarely seen. Alveolar macrophages exist at the tissue—air interphase, where they encounter inhaled pollutants and microorganisms. Despite encountering these microbes, these macrophages rarely display inflammatory properties and trigger adaptive immune responses.
Alveolar macrophages exist in an environment with a high partial pressure of oxygen as compared to the other mononuclear phagocytes of the body. As a consequence, alveolar macrophages have metabolic properties different than macrophages in other sites.
Their basal glucose consumption and respiratory rate is greater than those of all other phagocytes studied However, unlike phagocytes from other sites, they have a poor respiratory burst and little increase in hexose monophosphate shunt activity in response to soluble stimuli or phagocytosis Rat alveolar macrophages have high levels of cytochrome oxidase and low levels of the glycolytic pathway enzymes pyruvate kinase and phosphofructokinase when compared to peritoneal macrophages.
This particular enzyme phenotype in alveolar macrophages can be changed to that of peritoneal macrophages by incubating the cells in relatively anaerobic conditions in vitro Alveolar macrophages contain and secrete numerous enzymes typical of mononuclear phagocytes. The elastolytic enzyme activity of alveolar macrophages possibly a cathepsin B is poorly inhibited by the natural protease inhibitors of serum, while that of neutrophils is well inhibited This suggests that macrophages of the lung may be more important in elastin degradation than are neutrophils.
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Numerous environmental agents can alter alveolar macrophage function Cigarette smoke is one of the most important toxins to which alveolar macrophages are exposed and contains many materials in the particulate and vapor phases. Smokers have increased numbers of alveolar macrophages , , and cells from smokers show several abnormalities. The needlelike structures may represent ingested kaolinite or aluminum silicate from the cigarettes Cells from smokers spread more on glass and have more lamellipodia and filipodia than do those of nonsmokers These enzymes are important in the pathogenesis of pulmonary emphysema.
Alveolar macrophages from smokers also have impaired synthesis of RNA and protein , increased glucose utilization , increased hydrogen peroxide production, increased hexose monophosphate shunt activity, and reduced levels of glutathione peroxidase In vitro cigarette smoke exposure in high amounts impairs various functions of macrophages Also, alveolar macrophages contain the enzyme aryl hydrocarbon hydroxylase, and it is increased in macrophages from smokers , This enzyme transforms carcinogenic, polycyclic aromatic hydrocarbons into less dangerous hydrophilic compounds.
There may be a relationship between the inducibility of this enzyme and the susceptibility to lung cancer Pulmonary macrophages are important in specific immunologic reactions because of their processing of inhaled antigens and interactions with lymphocytes Interleukin-1, with its multiple effects, may be important in many different physiologic and pathologic conditions in the lungs Interleukin-1 is a mitogen for fibroblasts.
Alveolar macrophages interacting with silica or asbestos have been noted to contain or secrete a factor that enhances fibroblast proliferation and collagen synthesis , , suggesting that interleukin-1 may play a role in the fibrosis seen in humans with silicosis and asbestosis.
Chemokines produced by macrophages may also be important in the pathogenesis of fibrotic lung disease Splenic macrophages are present both in the red and the white pulp The red pulp is composed almost exclusively of macrophages involved in the phagocytosis and destruction of blood cells. Although the precise routes and dynamics of cellular movement within and through the spleen are not fully understood, red pulp macrophages apparently emigrate there through the fenestrations of the basement membranes of the splenic sinuses, and occasionally can be seen extending their pseudopods through these fenestrations, possibly interacting with blood elements In the white pulp, the macrophages are much less frequent and are found in the germinal centers, where occasionally they are seen phago-cytizing lymphocytes White pulp macrophages are presumably involved in antigen processing and generation of the immune response.
Red pulp macrophages contain numerous inclusions including phagocytized erythrocytes, neutrophils, eosinophils, and platelets , Splenic macrophages have receptors for the Fc portion of IgG and for complement , express antigens typical of mononuclear phagocytes at other sites , and contain ferritin and hemosiderin Many of the labeled cells are spread along the base of the epithelial cells, apparently underlying the basement membrane.