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(Journal of Leukocyte Biology. 2002;72:621-627.)
© 2002 by Society for Leukocyte Biology

The mononuclear phagocyte system revisited

David A. Hume, Ian L. Ross, S. Roy Himes, R. Tedjo Sasmono, Christine A. Wells and Timothy Ravasi

Institute for Molecular Bioscience, University of Queensland, Australia

Correspondence: David A. Hume, Institute for Molecular Bioscience, School of Molecular and Microbial Sciences, Molecular Biosciences Bldg., University of Queensland, Q4072, Australia. E-mail: D.Hume{at}imb.uq.edu.au

TOP ABSTRACT INTRODUCTION EXPRESSION OF THE CSF-1R... CRACKS IN THE FABRIC... "ACTIVATION," PLASTICITY,... CONCLUSIONS REFERENCES

 
The mononuclear phagocyte system (MPS) was defined as a family of cells comprising bone marrow progenitors, blood monocytes, and tissue macrophages. In this review, we briefly consider markers for cells of this lineage in the mouse, especially the F4/80 surface antigen and the receptor for macrophage colony-stimulating factor. The concept of the MPS is challenged by evidence that there is a separate embryonic phagocyte lineage, the blurring of the boundaries between macrophages and other cells types arising from phenotypic plasticity and transdifferentiation, and evidence of local renewal of tissue macrophage populations as opposed to monocyte recruitment. Nevertheless, there is a unity to cells of the MPS suggested by their location, morphology, and shared markers. We discuss the origins of macrophage heterogeneity and argue that macrophages and antigen-representing dendritic cells are closely related and part of the MPS.

Key Words: macrophage • colony-stimulating factor • microarray • lipopolysaccharide • F4/80 • c-fms

TOP ABSTRACT INTRODUCTION EXPRESSION OF THE CSF-1R... CRACKS IN THE FABRIC... "ACTIVATION," PLASTICITY,... CONCLUSIONS REFERENCES

 
The mononuclear phagocyte system (MPS) is defined as a population of cells derived from progenitor cells in the bone marrow, which differentiate to form blood monocytes, circulate in the blood, and then enter tissues to become resident tissue macrophages [¹ ]. The original advocate of the MPS classification placed considerable emphasis on the view that the majority of cell division in this lineage occurs in the monoblast, promonocyte stage and that local proliferation of mature macrophages was a minor mechanism in the maintenance of resident tissue macrophage numbers [¹ ]. Mononuclear phagocytes as defined originally shared many characteristics that had been studied in detail for many years, including 1) morphology and ultrastructural features observed by light and electron microscopy; 2) expression of certain enzymes that could be detected by histochemical staining (notably, nonspecific esterase, lysosomal hydrolases, and ectoenzymes); and 3) nonspecific uptake of particles, such as latex or colloidal carbon, and specific endocytic receptors especially for the Fc portion of immunoglobulin and for complement-coated particles.

A major step forward in investigation of the MPS came with the arrival of monoclonal antibody technology. In mouse, rat, and human, hybridomas were made that produced antibodies directed against antigens expressed solely on the surface of presumptive MPS cells. Others have reviewed the biology and usefulness of such markers [² ]. One such antibody, F4/80, was examined exhaustively [³ ]. The F4/80 antibody recognizes a member of a family of genes also including human epidermal growth factor (EGF) module-containing mucin-like hormone receptor 1 and human CD97 [⁴ ]. Members of the EGF-TM7 family are characterized by a variable number of NH₂-terminal EGF domains and seven transmembrane-spanning hydrophobic regions resembling the G protein-coupled peptide hormone receptor family. The intervening years since description of F4/80 have not revealed a clear function. The knockout mouse has no clear phenotype [⁵ ], but this could be related to the presence of a related gene with overlapping expression [⁶ ]. Clues as to function may come from CD97, for which a cellular ligand has been identified (CD55) [⁵ ].

F4/80 antigen is present on the cell surface of a family of cells that includes all well-defined members of the MPS in the mouse. A unique advantage of the F4/80 antibody was that it bound to an epitope that was resistant to glutaraldehyde fixation and paraffin embedding. For this reason, it was possible to produce high quality images from perfusion-fixed mouse tissues. The full impact of these images was not evident at the time, because they could not be reproduced in print. A large collection of them has been scanned and deposited in a database at www.imb.uq.edu.au/groups/hume/tissuesDB3.html, together with annotation and some comments about possible functions.

There is an inherently circular logic to the use of a single antigenic marker to define a cell type, which in turn defines the specificity of the marker. Nevertheless, the family of F4/80-positive cells had many features in common, regardless of their tissue location. They tend to be highly ramified, and like macrophages in cell culture, they spread on surfaces. The major surface location that is evident in an exhaustive examination of F4/80 location in all tissues is the basement membrane. Every epithelial and endothelial surface in the body has a substantial F4/80-positive cell population spread in the plane of the underlying basement membrane. In stratified epithelia and in the simple epithelia of all secretory ducts, these cells cross the basement membrane and extend processes between the epithelial cells. Associated with epithelia, and indeed in many other locations in the body, the distribution of the F4/80-expressing cells is clearly not random; they occupy a precise anatomical niche. The most striking examples, evident because the pattern is two-dimensional, are the Langerhans cells (LC) of the skin and retinal microglia. In the epidermis of the mouse ear, LC interdigitate among a group of 12–13 proliferating, basal keratinocytes at the center of a precise hexagonal array of structural units called squame piles. In the retina, a precise hexagonal array of microglia spreads in the plexiform layers separating the neuronal nuclear layers. A similar order and strict numerical relationship are evident when one views a section that grazes the surface of an epithelial sheet. Examples of each of these locations are included in the database. A precise anatomical location suggests some purpose relating to physiology rather than immunity, a quite distinct view from the concept of the wandering phagocyte. One possible role would be in the phagocytosis and elimination of dying cells, but in sites where physiological apoptosis occurs, it is clear that newly recruited blood monocytes are involved [^{7 8 9} ]. A second alternative is that tissue macrophages secrete regulators that alter the physiological functions and differentiation of neighboring cells.

The clearest evidence of such roles comes from the study of op/op mice, which have a mutation in the gene encoding the key macrophage growth factor, colony-stimulating factor type 1 (CSF-1) [⁸ , ⁹ ] or, more recently, an introduced mutation in the CSF-1 receptor (R; c-fms) locus [¹⁰ ]. In fact, mice with these mutations also validate the view that F4/80-positive cells have a common origin. The op/op mice have substantial deficiencies in many F4/80-positive tissue-macrophage populations [⁸ , ⁹ ]. The importance of these cells is evident from the male and female infertility and gross sensory neuron dysfunction in op/op mice (see refs. [⁸ , ⁹ ]). Interestingly, CSF-1-deficient mice are not completely devoid of F4/80-positive cells in any location, and some populations are unaffected [⁸ , ⁹ ]. Furthermore, the number of "CSF-1-dependent" cells, particularly osteoclasts, can increase with age, apparently in part as a result of compensatory actions of other growth factors, vascular endothelial growth factor-A [¹¹ ], and flt3-ligand [¹² ].

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Although the F4/80 antigen is widely distributed, there are some major macrophage-like cell populations in which it is difficult to detect, including macrophages of the lung and lymphoid organs [³ ]. Given the key function of CSF-1 in macrophage proliferation, differentiation, and survival, we reasoned that the CSF-1R would provide an alternative surface marker. We therefore spent a several years defining the key elements required for accurate transcriptional regulation of c-fms, the gene encoding the CSF-1R [^{13 14 15 16} ]. A 7.2-kb promoter region element of the gene, including a key enhancer in the first intron, was found to direct appropriate expression of an enhanced green fluorescent protein (EGFP transgene) in transgenic mice. In these mice, which we have dubbed MacGreen mice, the EGFP transgene product is expressed in a pattern that overlaps almost completely with that of the F4/80 antigen [¹⁷ ] (see also additional data at www.imb.uq.edu.au/groups/hume, under data). Additionally, EGFP is expressed in myeloid precursors in the marrow, on blood monocytes, and in macrophage-like cells of the lung interstitium and alveolar spaces. This marker enables the purification of tissue macrophage populations following enzymatic tissue disaggregation, providing a new avenue to their phenotypic analysis.

Like F4/80, EGFP is also expressed at very high levels in LC (Fig. 1 ), which are unaffected by the op/op mutation in the CSF-1 gene. LC are regarded as immature precursors of antigen-presenting myeloid DC [¹⁸ , ¹⁹ ]. The EGFP transgene was also detected uniformly on classical splenic DC, defined by expression of CD11c, and on bone marrow-derived DC produced by cultivation in granulocyte macrophage (GM)-CSF [¹⁷ ]. The relationship between macrophages and DC has been a matter of as much debate as the original definition of the MPS. More recently, it has become evident that the poorly endocytic, specialized antigen-presenting cell phenotype of the archetypal DC arises following phagocytic activation of a cell that by most accepted criteria would be called a macrophage [¹⁸ , ¹⁹ ]. There are relatively few markers that "distinguish" macrophages and DC, and much of the distinction between the two cell types is based on the circular logic inherent in definition by any marker. The EGFP marker expression in MacGreen mice suggests that macrophages and myeloid DC are united by their ability to sustain activity of the c-fms promoter [¹⁷ ]. This conclusion is consistent with recent reports on the expression of c-fms on shared macrophage/myeloid DC/osteoclast progenitors in the marrow [²⁰ , ²¹ ]. In our view, it remains questionable whether there is any real basis for a clear dichotomy between the mononuclear phagocyte cell types or whether there is a continuum of cellular phenotypes that invites classification at the extremes but lacks a clear, distinguishing boundary.

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Figure 1. The green fluorescent protein transgene driven by the c-fms promoter provides a marker for mononuclear phagocytes. The panels show representative tissue sections of tissues rich in mononuclear phagocytes taken from the MacGreen mice in which expression of EGFP is driven by a 6.7-kb c-fms promoter [15 ]. LC in the skin (A) and resident tissue macrophages in the liver/Kupffer cells (B), in the spleen (C), and lung (D). RP, Red pulp; WP, white pulp.

TOP ABSTRACT INTRODUCTION EXPRESSION OF THE CSF-1R... CRACKS IN THE FABRIC... "ACTIVATION," PLASTICITY,... CONCLUSIONS REFERENCES

 
Embryonic phagocytes
In the embryo, the first cells expressing the CSF-1R (c-fms) mRNA arise in the yolk sac and rapidly thereafter appear in the head and spread through the embryo via the developing circulation [²² , ²³ ]. They are clearly actively involved in phagocytosis of dying cells. Curiously, these cells do not appear to arise within the classical haematopoietic islands of the yolk sac, do not pass through a classical monocyte stage of differentiation/morphology or antigen/gene expression (for example, expression of the S100A8 marker), and do not express mature macrophage markers such as F4/80 (reviewed in ref. [²⁴ ]). Additionally, they lack expression of the key macrophage transcriptional regulator, PU.1 [²³ ], and their appearance is unaffected by a mutation in this gene that blocks development of myeloid cells in the liver. The PU.1-independent phagocytes are maintained through embryonic development. The question is whether they are still retained in the adult and perhaps constitute a source of tissue macrophages with a capacity for self-renewal. It is interesting that there is very clear genetic evidence in zebrafish for two independent populations of "mononuclear phagocytes." Consistent with their expression of c-fms in the mouse, the migration of embryonic phagocytes is affected by the panther mutation in the zebrafish fms ortholog [²⁵ , ²⁶ ].

Local proliferation and renewal
van Furth [¹ ] took the view that tissue macrophage populations do not self-renew and that the most replenishment of these populations arises from monocyte recruitment. A more modern approach to delineating the origins of tissue macrophages has been the use of bone marrow transplantation with genetically marked marrow. One criticism of such studies is that cells undergoing local proliferation may also be affected by radiation required for marrow transplantation so that marrow-derived cells may occupy niches that arise only following such trauma. In any case, a recent study examined reconstitution of tissue macrophage populations following engraftment with lacZ-expressing donor bone marrow cells. Where bone marrow colony-forming cells and splenic macrophages were mainly of donor origin within one month, only 61% of lung and liver macrophages were apparently replaced by donor cells after one year, and microglia were even less likely to be turned over [²⁷ , ²⁸ ]. The interpretation favored by the authors is that tissue macrophages turn over slowly. An alternative explanation is that not all tissue macrophages are replaced by blood monocytes in the steady state and that local proliferation makes a significant contribution.

Transdifferentiation
The current opinion of the MPS views this family of cells as being quite distinct from any other cell types in terms of function and origin and as derived from a unique hematopoietic stem cell. This view is being challenged by a deluge of data implicating bone marrow-derived stem cells in production of neurons, hepatocytes, renal epithelial cells, and numerous other cell types [^{29 30 31 32 33} ]. One might accommodate these observations by proposing the existence of a circulating bone marrow-derived mesenchymal stem cell pool, but much of the data suggest they can derive from purified haematopoietic progenitors. There is quite compelling evidence that mature blood monocytes and inflammatory macrophages can transform into vascular elements including endothelial cells, myofibroblasts, and smooth muscle cells [^{34 35 36 37 38} ]. The full extent of their ability to transmogrify is currently unknown, but the possibility that monocytes are actually pluripotent and can differentiate into many other cell types cannot be eliminated based on available information. Gene expression studies (see below) encourage this view. If monocyte-macrophages can transdifferentiate, why not the reverse pathway? In the worm c-elegans, apoptotic cells are engulfed by neighboring cells, which acquire phagocytic activities. Some key genes involved, Ced-6 and Ced-7, have mammalian orthologs that are expressed in circulating phagocytes and are involved in apoptotic cell recognition [³⁹ , ⁴⁰ ]. However, in mice with a deficiency in macrophage production as a result of mutation in the PU.1 gene, neighboring cells can apparently substitute, albeit less effectively, in clearance of dying cells in areas of rapid cell death [⁴¹ ]. The pathway may be accelerated in malignancy, where many tumor cells express the CSF-1R and can also express other macrophage-associated phenotypic characteristics [⁴² ].

TOP ABSTRACT INTRODUCTION EXPRESSION OF THE CSF-1R... CRACKS IN THE FABRIC... "ACTIVATION," PLASTICITY,... CONCLUSIONS REFERENCES

 
What is in a name? The purpose of defining a cell lineage such as the MPS is to permit predictions about biological function based on detection of that cell type in a particular location. When we detect large numbers of F4/80-positive cells in a lesion, we presume that they will be capable of secreting inflammatory cytokines and eliciting a certain kind of tissue damage. Such predictions are based on an underlying assumption that there is a level of consistency to the ways in which sets of genes are coexpressed to define a transcriptional phenotype. We, and others [^{43 44 45} ], have addressed that question by examining comprehensive gene expression profiles of isolated mouse macrophage populations [^{43 44 45} ]. In collaboration with the RIKEN Genome Sciences Center in Japan, we compared the expression profiles of isolated mouse macrophages with the published profile of genes expressed in 49 mouse tissues [⁴⁶ , ⁴⁷ ]. Full details of this analysis and the raw data will be presented elsewhere (C. A. Wells et al., unpublished results) and uploaded to our Website at www.imb.uq.edu.au/groups/hume. The most important conclusion from this study for definition of the MPS is that macrophages segregated to a separate branch on a Stanford Gene Tree analysis related to hematopoietic tissues such as spleen (which contain numerous macrophages) but were clearly distinct in their expression profile. The other conclusion is that the cells we call macrophages can exhibit a broad range of gene expression steady states. We examined the response of macrophages to the archetypal microbial regulator of their gene expression lipopolysaccharide (LPS). The change in gene expression profile in LPS-stimulated macrophages is very large. In fact, as shown in Figure 2 , there are very few genes that do not change their level of expression. Those genes that were expressed initially at high levels were mainly repressed by LPS, as if to accommodate the new spectrum of induced genes. The full spectrum of LPS-inducible genes in mouse macrophages is currently being dissected, and we will assemble that information on our Website. The complexity of LPS-inducible gene regulation can actually be inferred from the literature. We have assembled a list of genes that are known to be induced by LPS in macrophages from a survey of the literature (Table 1 ). These genes provided a historical, validated set for the array set. Others have already shown that the set of inducible genes in macrophages is quite distinct and only partly overlapping if one examines stimuli such as virus, bacteria, or yeast challenge [⁴⁸ ]. The documented set of stimuli can alter macrophage gene expression numbers into the hundreds and is beyond the scope of this review. We can presume that each elicits its own unique pattern. In addition, there are combinatorial effects of which the archetype is the combined response of macrophages to T cell products [e.g., interferon- (IFN-)] and LPS [⁴⁹ ]. Even other microbial products that act via other Toll-like receptors, closely related to the LPS-signaling component Tlr4, have additive and distinct effects on macrophage gene expression [⁵⁰ ] and can be affected in quite opposite directions by agonists such as CSF-1 [⁵¹ ].

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Figure 2. Global changes in gene expression stimulated macrophages. Bone marrow-derived murine macrophages were stimulated with LPS; RNA was extracted and was used to probe a 20,000 element cDNA microarray. The picture shows the distribution of expression levels of the 20,000 genes across five time points after exposure to LPS. Each gene is colored according to the signal intensity measured at time 0. Red indicates the gene was highly expressed at time zero; yellow, moderately expressed; and blue, not expressed at time 0. With time of exposure to LPS, most of the blue elements (initially undetectable) are induced across the time course, and most of the red elements (initially expressed at high levels) are repressed. Very few elements remain static, indicating LPS has a profound effect on the macrophage transcriptome (C. A. Wells, T. Ravasi, D. Hume, et al., unpublished results).

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Table 1. Gene Regulation by LPS in Mouse Macrophages

The phenotypic plasticity of macrophages that can be generated in vitro presumably underlies the wide range of phenotypes observed in vivo. Resident tissue macrophages adapt to their local environment to perform specific functions. Much of the literature on resident macrophages, for example those of the lung and liver [⁵² ], testis [⁵³ , ⁵⁴ ], and brain (the microglia; refs [^{55 56 57 58} ]), focuses on their role as sensors in inflammation and tissue regeneration. Nevertheless, there is increasing recognition of their trophic interactions with the other resident cells in each organ. As noted previously [⁵⁹ ], macrophages are strategically located in organs such as the kidney, pancreas, and many endocrine organs to monitor physiological processes and contribute to homeostasis. Almost any local disturbance of tissue normality, be it infection, normal cell turnover or wounding, immune response, or malignancy, causes rapid recruitment of macrophages. The nature of the recruitment process is beyond this review. Recruited macrophages exhibit many phenotypic differences from resident tissue macrophages. The generic term "macrophage activation" is commonly used to describe this process, but the nature of an "activated macrophage" population depends on the nature of the recruiting stimulus and the location. A PubMed search (macrophage activation and review) generates thousands of articles, each dealing with a specific disease focus or etiological agent in a particular organ. Broadly speaking, there has been a focus in the literature on a dichotomy between the cells recruited by a sterile stimulus, the macrophages associated with wound repair, regeneration, and also foreign body responses and the cells recruited by immunological stimuli. The latter are commonly called "activated macrophages" and are ascribed a greater destructive potential than resident or "elicited" cells [⁵⁹ ]. With the availability of better markers and more comprehensive analyses, these definitions are less useful, and it becomes more relevant to rigorously link the definition of the population phenotype to the inducing stimulus and the location. Every macrophage population is likely to be different. An interesting side issue is the extent to which resident and recruited macrophages can be said to have differentiated in the sense that they become less plastic with time in a specific location. Resident macrophages certainly can become "activated." For example, activation of microglial cells in particular is regarded as a significant event in many brain diseases [^{55 56 57 58} ]. A related issue is what happens to recruited macrophages once the recruiting stimulus has been resolved (which is the point of the infiltration). Many of the macrophages certainly die in situ. Apoptotic cells are themselves a major stimulus to macrophage recruitment [⁶⁰ , ⁶¹ ], but this is a process aimed at resolution and regeneration and a part of normal tissue homeostasis. Resident macrophages in defined locations are probably themselves replaced by being engulfed by their replacement. Inflammatory cells enter draining lymphatics to acquire new functions as antigen-presenting cells or perhaps to die and be eliminated there. There is no evidence of which we are aware of recycling into the circulation and/or reacquisition of a monocyte-like phenotype.

To add one additional layer of complexity, the set of inducible genes observed in mouse macrophages with a defined agonist such as LPS is influenced by genetic background, and cDNA microarrays are starting to give an insight into the full extent of this variation. In a published study, we compared BALB/c and SJL mice, which differ among other things at the Bcg locus, which controls susceptibility to intracellular pathogens [⁴⁵ ]. Others have also observed global differences in gene regulatory profiles in macrophages from different strains and have linked them to genetic tendencies to generate T helper cell type 1 (Th1) or Th2-dominated, T cell-mediated immune responses. They have even gone so far as to coin the terms M1 and M2 responses for macrophages [⁶² ]. Our own microarray studies of a wider range of strains suggest that each has its own unique LPS-inducible gene expression profile, including an idiosyncratic set of genes for which there is no detectable expression (unpublished results). This kind of functional polymorphism is actually not so surprising, given the diversity in immunoglobulin, T cell receptor, major histocompatibility complex (MHC), and natural killer (NK) cell receptor genes. A functional innate immune system is required only when a pathogen challenges. By definition, a successful pathogen evades the innate immune system, and mammalian hosts are under strong selection pressure to deal with the full diversity of possible pathogen evasion strategies.

If each mammalian host presents a different challenge to a pathogen because of genetic diversity, each individual macrophage may also be unique. The majority of inducible genes in a macrophage population exposed to LPS or other microbial challenge are expressed only in a subset of cells. Others have favored determinist explanations, including differences in environment such as exposure to different combinations of cytokines and growth factors during macrophage differentiation in the bone marrow and tissue as described above [⁶³ , ⁶⁴ ]. However, when one starts to examine larger gene sets, the range of combinations of genes starts to challenge credible determinist explanations and definitions of "subpopulations." We have argued that LPS-inducible gene activation (and indeed all transcriptional regulation) is a stochastic process. At the single cell level, individual alleles are expressed or they are not, and gene activation is best described in terms of an increase in frequency or probability of expression [⁶⁵ ]. We have provided evidence that gene-autonomous, transcriptional probability contributes to the individual diversity of LPS-inducible gene expression in macrophages in a population [⁴⁴ ]. Where the acquired immune system generates diversity by recombining genomic segments, individual macrophages might present a challenge to a pathogen by expressing a partly random combination of the thousands of inducible host-defense genes.

TOP ABSTRACT INTRODUCTION EXPRESSION OF THE CSF-1R... CRACKS IN THE FABRIC... "ACTIVATION," PLASTICITY,... CONCLUSIONS REFERENCES

 
By virtue of their genetic background, tissue environment, and chance, individual members of the MPS differ greatly from each other. However, despite these provisos, there remains a degree of unity to the MPS of an adult animal, as we currently understand it, and the concept put forward by van Furth [¹ ] has largely survived the test of time. Markers such as F4/80 and c-fms (or the EGFP transgene) define populations of cells that are united by location, morphology, and function. The c-fms marker may provide the most definitive marker for a population of cells that best fits the definition of the MPS, and that finding probably reflects the fact that the MPS arises from a population of cells that is responsive to, if not dependent on, the growth factor CSF-1.

Received March 14, 2002; revised May 7, 2002; accepted May 13, 2002.

TOP ABSTRACT INTRODUCTION EXPRESSION OF THE CSF-1R... CRACKS IN THE FABRIC... "ACTIVATION," PLASTICITY,... CONCLUSIONS REFERENCES

 

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