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1076 Part VIII: Monocytes and Macrophages Chapter 68: Production, Distribution, and Activation of Monocytes and Macrophages 1077

MATURATION AND DIFFERENTIATION OF expansion, and their genetic elimination has no effect on the lineage.
MONOCYTES AND MACROPHAGES M-CSF promotes survival as well as growth and differentiation of mac-
rophages, exclusively, acting through a specific receptor (CSF-1R),
22
23
The classic studies of Lewis and Lewis in 1926, Maximow in 1932, encoded by the protooncogene c-FMS, which has been extensively used
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and Ebert and Florey in 1939, showed that monocytes transform into as a lineage marker for fluorescence-activated cell sorting (FACS) analy-
macrophages and multinucleated giant cells in vitro. Macrophages can sis (CD115) and transgenesis. 27,28 The role of M-CSF has been reviewed
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be produced from monocytes or hematopoietic progenitor cells culture and its role in macrophage and osteoclast development is illustrated in
in cytokines, such as GM-CSF or M-CSF. Fig. 68–2. The naturally occurring mouse mutant, op/op, gives rise to
The alterations of ultrastructure during transformation into mac- M-CSF deficiency and osteopetrosis, with marked or partial deficiency
rophages, epithelioid cells, and giant cells have been described using in monocyte and selected tissue macrophage populations; DC num-
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purified populations of monocytes and in vitro culture techniques. bers are unaffected. Unlike PU.1 deficiency, the op/op mouse is viable,
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As the monocyte matures into the macrophage, the cell enlarges in though its reproductive ability is impaired, because M-CSF also plays an
size, and the lysosomal content and the amount of hydrolytic enzymes important role in the reproductive system. Uterine epithelium is a rich
within the lysosomes (e.g., phosphatases, esterases, β-glucuronidase, source of M-CSF, inducing monocyte-macrophage recruitment, growth
lysozyme, arylsulfatase) increase. At the time, the size and number and differentiation, and upregulating scavenger receptor (SR) expres-
of mitochondria increase, their energy metabolism increases con- sion, cell adhesion, and endocytosis of modified low-density lipopro-
comitantly. Production of lactate also increases. The Golgi complex, teins and other polyanionic ligands. M-CSF is produced in a soluble and
which packages lysosomes, increases in size and vesicle complexity membrane-bound forms, is present in plasma, and has been implicated
(Chap. 67). Several stimuli induce formation of multinucleated giant in atherosclerosis and tumor-dependent recruitment of monocytes and
cells from monocytes. 26 macrophages. The size of the growth burst induced by M-CSF depends
on the stage of differentiation of the target cell, decreasing markedly as
Growth Factors the precursors mature into monocytes and macrophages. Adhesion and
M-CSF and GM-CSF are the major growth factors implicated in inflammatory stimuli enhance the response to growth factors and can
monocyte and macrophage differentiation. Other cytokines, such as result in macrophage proliferation at peripheral sites, for example, in
interleukin (IL)-3 and IL-4, result in minimal monocyte proliferative granulomata.

Figure 68–2. Regulation of macrophage and osteoclast development by macrophage colony-stimulating factor (M-CSF). Circulating M-CSF, pro-
duced by endothelial cells in blood vessels, together with locally produced M-CSF regulates the survival, proliferation, and differentiation of mononu-
clear phagocytes and osteoclasts. The cytokine synergizes with other hematopoietic growth factors (HGFs) to generate mononuclear progenitor cells
from multipotent progenitors, and with receptor activator of nuclear factor-κB ligand (RANKL) to generate osteoclasts from mononuclear phagocytes.
Brown arrows indicate cell differentiation steps; blue arrows indicate cytokine regulation. (Used with permission of S. Seif, GraphisMedica, 2014.)

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