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Arterioscler Thromb Vasc Biol. Author manuscript; available in PMC Jul 1, 2012.
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PMCID: PMC3117206
NIHMSID: NIHMS291231

The spatial and developmental relationships in the macrophage family

Abstract

Ralph van Furth and Zanvil A. Cohn proposed, in their classic 1968 paper, that bone marrow-dwelling promonocytes differentiate to monocytes, which then intravasate, circulate and, upon tissue entry, differentiate to sessile macrophages. Since then, understanding of the macrophage family relationship has undergone substantial enhancement and occasional revision. It is currently recognized that, in addition to their role in the bone marrow, hematopoietic progenitors circulate and give rise to their descendants in extramedullary niches. Monocytes, of which there are several subsets, are not merely circulating macrophage precursors, but participate in the immune response in their own right. Macrophages are highly heterogeneous and, recent studies indicate, can arise in the absence of a monocyte intermediate. These spatial and developmental relationships reveal a complex interactive network and underscore the importance of context in evaluating biological systems. The observations have significant implications for how we image, target and treat disease.

Keywords: hematopoietic progenitors, monocytes, macrophages

The purpose of van Furth and Cohn's experiments was to understand the in vivo relationship between “free and fixed mononuclear phagocytes in different parts of the body under normal, steady state conditions”1. It was already known that monocytes and macrophages exist, and that they participate in clearing foreign and infectious agents. It was also known that monocytes give rise to macrophages in inflammation. The in vivo origin and turnover of monocytes in the steady state, however, was not yet understood. Through a series of labeling and fate mapping studies the authors concluded that rapidly dividing bone marrow promonocytes give rise to circulating monocytes which differentiate to tissue macrophages.

This linear and spatially-constrained framework has influenced our thinking on how macrophage-lineage cells relate to each other. Numerous studies have shown that the bone marrow produces hematopoietic cells, and much research is currently devoted to understanding the cellular and molecular components that constitute the stem cell bone marrow niche. Monocytes and macrophages have, likewise, received considerable attention, which has yielded a rich and nuanced understanding of their participation in health and disease. It may therefore be instructive to revisit the two pivotal components of van Furth and Cohn's model. The first is topographic: monocytes circulate in the blood, whereas progenitors and progeny reside in tissue. The second is developmental: bone marrow progenitors give rise to macrophages through a monocyte intermediate. In this review, I will discuss a few aspects of progenitor, monocyte, and macrophage biology, illustrated in the Figure, focusing particularly on recent studies that have challenged these two assertions.

Figure
Topo-ontogenic map of the macrophage lineage

Hematopoietic progenitors: Protected dwellers or roving travelers?

Hematopoiesis occurs in the bone marrow of the healthy human or mouse. The bone marrow stem cell niche is a highly organized environment consisting of supporting cells and molecules that guide stem cells through phases of self-renewal, proliferation, differentiation, and mobilization26. Its various cellular components include mesenchymal stem cells, osteoblasts, adipocytes, endothelial cells, and macrophages. Osteoblasts, which derive from mesenchymal stem cells, produce hematopoietic cytokines and mediators that influence stem cell expansion, repopulating capacity, and retention79. Adipocytes, which are also of mesenchymal origin, regulate the bone-marrow environment, possibly through adiponectin10, 11 whereas CD169+ macrophages promote the retention of hematopoietic stem cells in the bone marrow niche12. Such accessory cells secrete cytokines, growth factors, chemokines, and other molecular mediators and, together with intrinsic stem cell factors1316 contribute to the bone marrow's role as a housekeeping site of leukocyte production.

Blood transplantation experiments in mice provided the first evidence, in 1962, that hematopoietic stem cells (HSC) circulate17. It was later shown that HSC circulate freely and can reengraft vacant bone marrow niches18, 19. The mechanism behind HSC mobilization is not yet clear but is known to involve G-CSF, a growth factor long recognized in the clinic for its mobilizing activity. G-CSF activates neutrophils, which then secrete neutrophil elastase and cathepsin G. The proteases function in the bone marrow in at least two ways: first, they sever interactions between stem and stromal cells by cleaving VCAM-120; second, they interfere with the stromal-derived factor (SDF1)-CXCR12 chemokine axis that otherwise keeps HSC in the bone marrow niche21. More recent work has shown that the hormone noradrenaline contributes to HSC mobilization by decreasing CXCL12 transcription. This sympathetic nervous system hormone's intriguing role provides a mechanism for the robust circadian fluctuations of circulating HSCs and indicates that mobilization is a well-controlled process22.

Several non-mutually-exclusive theories about the physiological role of HSC mobilization have been proposed. According to one theory, HSC mobilization reflects bone marrow niche reconstruction5. This idea is based on the observation that the increase in HSC numbers in mice's peripheral blood during daylight correlates with higher bone-remodeling activity. Given the interdependence of bone and bone marrow, it is niche reconstruction that “sends HSCs out of their home”5. During periods of darkness, when mice are most active and bone remodeling is lowest, HSC return to the bone marrow and compete for space in the vacant niches. The system thus selects for the most fit cells capable of reengraftment19.

HSC may also mobilize for tissue immunosurveillance. In support of this concept, hematopoietic stem and progenitor cells (HSPC) have been shown to migrate to multiple peripheral organs and either differentiate to tissue resident cells or recirculate through the lymphatics back to the bone marrow23. HSPC egress from such extramedullary sites depends on sphingosine-1-phosphate, and is perturbed during inflammation. In order to evade phagocytosis in the harsh extramedullary environment, HSPC upregulate CD4724, a cell surface “don't eat me” marker that interacts with receptor SIRPα on scavenging macrophages. Together, these observations lend further support to the theory that HSC mobilization has an important physiological function beyond bone marrow niche reconstruction.

Extramedullary hematopoiesis is a well-documented phenomenon that occurs in both humans and rodents. In addition to supporting hematopoesis during development2527, extramedullary sites in the adult can, under certain conditions, generate platelets, erythrocytes, granulocytes, and mononuclear phagocytes2, 2832. There is an obvious advantage to outsourcing the production of terminally differentiated leukocytes to peripheral organs: HSPC that establish residence in a target organ can proliferate, generating many descendants. The process is self-sustaining and less dependent on constant replenishment of bone-marrow-derived non-proliferating cells, but it can also backfire, as documented in various genetic and myeloproliferative diseases3336. Despite the many situations where extramedullary hematopoiesis occurs, its orchestrating mechanisms and the scope of its influence remain largely unexplored. One study, aiming to decipher what an extramedullary niche may look like, proposed that, in the absence of osteoblasts, HSC settle adjacent to the sinusoidal endothelium37. HSPC retention and survival may depend on S1P23 and CD4724, respectively, but other supporting cells and molecules remain undescribed. It is also unclear whether extramedullary hematopoiesis can give rise to circulating monocytes that populate tertiary sites, or whether the process necessarily differentiates cells to their terminal tissue phenotype. Future studies will need to investigate the functional and compositional properties that characterize the extramedullary niche, compare progeny made in different locations, and investigate whether such processess participate in various acute and chronic diseases.

Monocytes: Indifferent progenitors or resolute gatekeepers?

Monocytes are defined as large bone-marrow-derived circulating mononuclear phagocytes that give rise to macrophages and dendritic cells3842. The cells arise in the bone marrow from a dedicated clonogenic progenitor43, 44, and enter the circulation via CCR245, 46. In the blood, monocytes circulate freely for a few days before extravasating or dying4749, and in vitro, they rapidly differentiate. Monocytes are thus transitional sentinels that bridge the gap between progenitors and terminally differentiated macrophages.

Leukocyte intravasation is well described, and includes such processes as capture, rolling, arrest, adhesion, crawling, and transendothelial migration50. In order to enter tissue, leukocytes cross several layers: they pass through a confluent layer of endothelial cells and a non-confluent layer of pericytes. Penetration of the endothelium occurs either by transcellular migration (through cells) or by paracellular migration (between cells)51, although the relative importance of transcellular migration is not known. The entire process involves a myriad of adhesion molecules and various protrusive and hydrostatic forces52.

Leukocyte engagement with the endothelium does not necessarily lead to transmigration. Mouse and human monocytes, for example, patrol the endothelium in the steady state53, 54. The process depends on LFA-1, does not follow the direction of blood flow, precedes extravasation, and is limited to Ly-6Clow monocytes in the mouse and CD14low monocytes in the human. (On monocyte heterogeneity, see38, 40, 55, 56.) The patrolling supports the idea that monocytes are sentinels that screen for injury or infection. It also indicates that monocytes are active gatekeepers of the inflammatory cascade. Neutrophils, the other myeloid circulating cells, have also been shown to crawl along the endothelium, but it is not yet clear how the two processes compare57, 58.

It is generally accepted that, once a monocyte transmigrates, it differentiates. It has therefore been surprising to discover that monocytes can also inhabit tissue without differentiating. Clusters of monocytes that are indistinguishable from their circulating counterparts inhabit the splenic red pulp59. The splenic monocytes are relatively immotile in the steady state, but in response to distant injury they can intravasate and populate distant tissues. This monocyte reservoir contributes not only to injury associated with myocardial infarction59, 60 and abdominal aortic aneurysm61, but has also been implicated in ovulation62, 63 stroke64, and several other conditions (our own unpublished observations). It is still not known how this reservoir is replenished and maintained, and it is possible that the spleen, perhaps by virtue of its open circulation, is uniquely suited to accommodate vast quantities of undifferentiated monocytes. Nevertheless, it is appealing to speculate that monocytes can enter and exit tissue without differentiating because it indicates that monocytes, as monocytes, influence the immune response outside of the blood.

Macrophages: Ontogenically uniform or altogether heterogeneous?

Given monocytes' image as progenitors, it is not surprising that their fate has received considerable attention. The list of tissues that monocytes are known to infiltrate is long. In the inflamed skin, Ly-6Chigh monocytes differentiate to Langerhans cells65. The inflamed brain sees Ly-6Chigh monocytes accumulate and give rise to microglia6668. A model of myocardial infarction reveals Ly-6Chigh and Ly-6Clow monocyte accumulation occurring in two phases. First, inflammatory Ly-6Chigh monocytes accumulate via CCR2, phagocytose dead cells, and secrete proteases. Then, four days later, reparative Ly-6Clow monocytes accumulate via CX3CR1 and contribute to granulation tissue formation69. In a non-ischemic model of skin injury, Ly-6Chigh monocytes accumulate and polarize to different macrophage phenotypes over time70. A model of heart transplantation shows Ly-6Chigh monocytes progressively infiltrating the allograft and contributing to a signature of organ rejection71, but the monocytes can also induce tolerance72. Studies of atherosclerosis indicate that Ly-6Chigh monocytes give rise to lesional macrophages73, while Ly-6Clow monocytes appear to differentiate to dendritic cells74. In adipose tissue, M1 macrophages appear to be of Ly-6Chigh origin75. Bacterial infection induces Ly-6Chigh monocytes to generate TNFα and iNOS, thereby becoming so-called TNFα/iNOS-producing dendritic cells, or TipDC76, 77. Lastly, there is now convincing evidence that monocytes can acquire dendritic cell morphology, localize in T cell areas, and stimulate adaptive immunity by presenting and cross-presenting antigen78. (For discussion on how macrophages and dendritic cells compare, see39, 79).

An enormous body of literature confirms that macrophages and dendritic cells have a role in diseases such as atherosclerosis, obesity and cancer8083, and many of these cells are known to derive from monocytes70, 73, 75. Whether monocytes or their subsets differentiate to specific macrophage or dendritic cell populations in the steady state is less clear. Recent work has shown that microglial cells arise from primitive Runx1+ resident progenitors and not from monocytes84. This surprising disconnect can also be observed between monocytes and dendritic cells. Even though dendritic cells can arise from monocytes during inflammation78, classical splenic dendritic cells49 and, presumably, Langerhans cells85 arise without a monocyte intermediate in the steady state. Collectively, these studies suggest that monocytes are not, by default, tissue-replenishing cells.

What then is monocytes' physiological fate? Data on this are scarce because it is difficult to conduct convincing monocyte tracking experiments and those that exist tend to focus on disease models. Perhaps, as van Furth and Cohn proposed, monocytes repopulate the peritoneal macrophage pool. This is not a very satisfying explanation when cell number and turnover kinetics are considered: if monocytes do indeed circulate briefly, then their turnover in the peritoneum should be very rapid and this is unlikely given the manifest morphological and phenotypic differences between the cells. It is more satisfying to think that, in the absence of differentation-inducing signals, monocytes circulate, patrol, and accumulate in reservoir sites. Unless they encounter a differentiation signal, they are simply eliminated through efferocytosis. If so, it may be that such efferocytosis-mediating machinery also regulates monocyte production. It is also remotely possible that monocytes give rise to other, unexpected phenotypes, although, again, the rate of monocyte turnover suggests such contribution to be minor. Clearly, there is a need for a systems-wide approach to dissect the monocyte life-cycle in its various spatio-functional contexts.

Concluding remarks

van Furth and Cohn's influential 1968 study has shaped our understanding of the spatial and developmental relationships between monocyte precursors, monocytes, and their progeny. Accumulating evidence indicates a more complex series of interactions than previously believed: progenitors circulate and differentiate in extramedullary niches; monocytes are not simply transitional; macrophages can develop without a monocyte intermediate. This complexity, which requires further attention to context, enriches rather than invalidates van Furth and Cohn's observations. Such complexity has implications for how we treat disease because understanding which cells interact, where they interact, and how they interact can illuminate which cells should be targeted, in what sites and for how long during treatment. Approaches that target the macrophage lineage either for imaging or treatment will require a nuanced understanding of the cells' distribution, function, and lifespan (on molecular imaging of macrophages, see 86). The insights may lead to tailored targeting strategies that discriminate between beneficial and harmful functions for which macrophages and their associated cells are known.

Acknowledgments

Sources of Funding This work was supported by NIH grant R01-HL095612 (to FKS).

Footnotes

Disclosures None.

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