Monocyte Ontogeny

Stages of Monocyte Differentiation

Monocytes originate in the BM from promonocytes, which constitute approximately 3% of the total cells in the normal BM (Fig. 1). Promonocytes have round nuclei and basophilic cytoplasm. Differentiation occurs rapidly, with a maturation time of 50 to 60 hours, associated with two rounds of replication and morpho logic maturation marked by progressive lobulation of the nucleus. Stress-induced release of monocytes occurs primarily through their premature release from the proliferating pool. Survival in the blood is short, approximately 8 to 72 hours. Monocytes then enter the tissues, where they develop into macrophages that may survive for 2 to 3 months. Tissue-resident macrophages are found in the lung (alveolar macrophages), liver (Kupffer cells), spleen, and central nervous system (glial cells).

Fig1. A PROMONOCYTE, MONOCYTE, MACROPHAGE, AND HISTIOCYTE. Promonocytes are rare in the bone marrow (BM) (A) and are more frequently seen during recovery or during marrow regeneration after chemotherapy or other insult. They are typically slightly folded and have nucleoli. The cytoplasm is moderately abundant and blue/gray with very faint granules. Monocytes seen in the blood (B) typically have more folded or horseshoe-shaped nuclei and more abundant gray cytoplasm frequently with vacuoles and rare granules. The macrophage (C) is seen in body fluid specimens such as peritoneal fluid or cerebrospinal fluid and resembles the blood monocyte. Tissue histiocytes are fixed in the tissues and are seen on tissue sections. The histiocyte shown (D) is stained with CD68 and is from a lymph node. It likely represents a dendritic cell in a germinal center. Monocytes in the BM can be more easily enumerated with a nonspecific esterase cytochemical reaction such as alpha-naphthyl acetate esterase, which gives an orange/brown reaction product (E).

Monocytes can also serve as precursors to a subset of dendritic cells. Dendritic cells are professional antigen-presenting cells that arise from both myeloid and lymphoid precursor cells. The myeloid subset of dendritic cells arises from a precursor that can alternatively differentiate into macrophages. Similar cells have been generated for immunotherapy by exposing peripheral blood monocytes to GM-CSF and IL-4 in vitro.

Markers of Monocyte Maturation

 Unique surface markers of monocyte maturation have been difficult to identify. In the mouse, the marker F4/80 was identified as a nearly universal marker of monocytes and macrophages; this antigen has been shown to be homologous to the human EGF module containing mucin-like hormone receptor 1. The function of this receptor is unknown because the knockout mouse has no phenotype. Monocyte precursor cells express the M-CSF receptor, lysozyme, the Fcγ receptor (II/III), and the scavenger receptor. Mature monocytes, like neutrophils, show high-level expression of CD11b/CD18. Following differentiation to macrophages, the cells acquire expression of macrosialin (CD68), a glycoprotein of unknown function that may play a role in lipoprotein metabolism. Macrophages also express sialoadhesin, a member of the sialic acid–binding receptor family. Although its precise function has not been proven, sialoadhesin mediates binding to sialic acid moieties on cell surfaces and probably plays a role in macrophage cell-cell and cell–extracellular matrix interactions.

CD14 is a major functional surface protein of the monocyte/macrophage lineage. CD14 is the receptor for LPS, leading to monocyte/macrophage activation. More recent studies have suggested that CD14 may also have a role in apoptosis.

Monocytes contain both primary (peroxidase-positive) and secondary (peroxidase-negative) granules. The primary granules of monocytes, like those of neutrophils, contain MPO. Secondary gran ule fusion with the membrane upon monocyte stimulation results in upregulation of Mac1 and p150, which are thought to play roles in adhesion and diapedesis of activated monocytes.

Control of Monocytopoiesis

Cytokine Regulation of Monocyte Proliferation and Differentiation

The primary regulator of mononuclear phagocyte production is colony-stimulating factor 1 (CSF-1; also known as M-CSF). Its effects are mediated by the high-affinity receptor tyrosine kinase CSF-1 receptor (CSF-1R), which was first identified as the gene product of the c-fms proto-oncogene. Alternative splicing of CSF1 results in five distinct mRNA transcripts and three isoforms of the CSF-1 protein: a secreted proteoglycan, a secreted glycoprotein, and a membrane spanning cell surface proteoglycan.

The phenotypes of Csf1-null mice and of mice harboring an inactivating mutation in the coding region of Csf1 (Csf1^op/op, osteopetrotic mice) are virtually identical; features include toothlessness, low body weight, low growth rate, defects in fertility, and deficient tissue macro phages. Compared with their wild-type littermates, splenic erythroid burst-forming unit and high-proliferative-potential colony-forming cell counts in both Csf1^op/op and Csf1^−/− mice were significantly elevated, supporting a negative regulatory role for CSF-1 in erythropoiesis and in the maintenance and proliferation of primitive hematopoietic progenitors. Plasma CSF-1 levels in CSF receptor–null (Csf1^−/−) mice were elevated 20-fold, consistent with previous reports demonstrating clearance of circulating CSF-1 by CSF-1R–mediated endocytosis. Despite their overall similarity, several phenotypic characteristics of the Csf1^−/−mice are more severe than those of the Csf1^op/op mice. These observations suggest that CSF-1 signals exclusively through CSF-1R, but CSF-1R may mediate other effects from CSF-1–independent activation.  

Signaling through CSF-1R appears to be critical for monocyte/ macrophage development. Although little is known about the events that lead to stimulation of a monocyte/macrophage–specific array of genes, it is clear that several transcription factors, probably stimulated by CSF-1–related signaling, play vital roles in the development of this lineage. It should be noted that the ability of phorbol esters to induce monocytic differentiation of myeloid cell lines through activation of the protein kinases Cα and Cδ suggests a role for the PKC pathway in monopoiesis.

IL-3, G-CSF, and tumor necrosis factor (TNF) have all been shown to synergize with CSF-1 in the proliferation of macrophages. G-CSF induces increased mobilization of monocytes as an indirect effect dependent on the presence of CSF-1. Monocytes have also been shown to have functional G-CSFRs, although G-CSF appears to function mainly to decrease monokine secretion rather than to increase monocyte proliferation.

Transcriptional Regulation of Monocyte Differentiation

Of the several transcription factors known to regulate the development of the monocyte/macrophage lineage, PU.1 appears to be the most significant because abrogation of PU.1 expression in PU.1-null mice results in perinatal lethality accompanied by the absence of mature monocytes/macrophages and B cells, and delayed and reduced granulopoiesis. A number of factors, most notably c-Jun, cooperate with PU.1 to regulate monocyte-specific genes.

c-Jun

The JUN proto-oncogene encodes the transcriptional activator protein AP-1. As an early response gene, JUN is rapidly and transiently activated in response to external proliferative signals. Expression of c-Jun as well as related family members JunB and JunD is upregulated during monocytic differentiation. In addition, overexpression of c-Jun in M1, U937, or WEHI-B D+ myeloid cell lines, as well as in myeloid progenitor cells, results in partial monocytic differentiation. However, Jun−/− fetal liver cells are capable of reconstituting hematopoiesis in syngeneic recipients, suggesting that c-Jun is not required for myeloid development. This finding may reflect a compensatory role played by other Jun family proteins.

During macrophage development, c-Jun serves as a coactivator of PU.1. Recent studies have revealed that downregulation of JUN by C/EBPα is necessary for granulocytic maturation and appears to be the mechanism through which C/EBPα blocks macrophage development. C/EBPα not only binds to the promoter of the JUN gene and decreases its expression but also binds to PU.1, inhibiting its activity. Such transcription factor cross-talk, resulting in subtle changes in the levels of transcription factors within a given lineage, appears to define a paradigm by which master regulators of lineage specification, such as C/EBPα and PU.1, direct lineage-specific development by directly upregulating lineage-specific genes and by blocking the progression of alternate lineages.

Other Transcription Factors Modulating Monocyte Development

 Egr-1. Egr-1 belongs to a family of zinc finger transcription fac tors and is expressed in a number of tissues and at various points in development, including the terminal stages of macrophage and neutrophil differentiation. Egr-1 is necessary for monocytic differentiation of myeloid cell lines U937 and M1 and prevents factor-induced granulocytic differentiation of HL60 and 32Dcl3 cells. In addition, ectopic expression of Egr-1 in myeloid BM progenitors results in an increase in the number of CFU-M at the expense of CFU-G pro genitors. However, mice lacking Egr-1 develop normal numbers of macrophages, a phenomenon attributed to the possible compensatory effects of other Egr family members.

C/EBPβ. As discussed earlier, expression of C/EBPβ increases during myeloid maturation and has been shown to be important for monocyte/macrophage gene expression and development.

MafB and c-Maf. The transcription factors MafB and c-Maf belong to a family of b-Zip factors that bind DNA as dimers. The Maf proteins can dimerize with members of other b-Zip family proteins including c-Jun, fos, and NF-E2 in erythroid cells. Ectopic expression of MafB in myeloblasts resulted in macrophage differentiation, whereas overexpression of c-Maf in HL60 and U937 myeloid cells resulted in monocytic differentiation.

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مواضيع ذات صلة

Eosinophil Production

Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression

Cytokine Regulation of Myeloid Proliferation and Differentiation

Neutrophil Granules and Their Content Proteins

Stages of Neutrophil Differentiation

T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity

Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion

Allogeneic Banked Cells

Clinical Results of Chimeric Antigen Receptor T Cells in Hematologic Malignancies

Types of Cellular Immunotherapy

Adoptive Immunotherapy of Cancer

Therapeutic Manipulation of T-Cell-Mediated Immunity