Review
Metchnikoff's policemen: macrophages in development, homeostasis and regeneration

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Over the past decade, modern genetic tools have permitted scientists to study the function of myeloid lineage cells, including macrophages, as never before. Macrophages were first detected more than a century ago as cells that ingested bacteria and other microbes, but it is now known that their functional roles are far more numerous. In this review, we focus on the prevailing functions of macrophages beyond their role in innate immunity. We highlight examples of macrophages acting as regulators of development, tissue homoeostasis, remodeling (the reorganization or renovation of existing tissues) and repair. We also detail how modern genetic tools have facilitated new insights into these mysterious cells.

Section snippets

An ever-expanding role for macrophages

Recent research has shed light on the diverse nature of myeloid cells. It is now recognized that subtypes of myeloid cells (see Glossary) have varied developmental origins, such as microglia which are derived from the embryonic yolk sac and not replenished by blood-derived monocytes [1]. Tissue macrophages, however, are derived from hematopoietic stem cells, but their expansion can either be due to local proliferation or infiltration, depending on the stimulus [2]. Although we often use the

Macrophages during development

Many studies have examined how macrophages or invertebrate phagocytes regulate developmental processes. Phagocytes certainly engulf dead cells, but they can also help decide which cells should apoptose [8]. More broadly, macrophages can also regulate developmental processes independent of apoptosis 9, 10. In the following sections we discuss how macrophages can act in all three contexts (Figure 2).

Macrophages during homeostasis

In terms of immune defense, the role of the macrophage in maintaining homeostasis is obvious. However, several recent papers have suggested that macrophages maintain homeostasis in other ways, including the regulation of leukocyte homeostasis, blood pressure physiology, reproductive functionality and lipid metabolism.

Macrophages during repair and regeneration

Tissue regeneration occurs either in response to injury or as a result of tissue ablation. During injury (such as ischemic, mechanical, toxic, immune-mediated or infectious), repair occurs before regeneration. By contrast, after tissue ablation (such as partial hepatectomy or digit amputation), regeneration occurs without a repair phase. Here, we address the role of macrophages in repair and regeneration.

Concluding remarks

A host of recent findings have expanded our understanding of the function of myeloid lineage cells far beyond passive engulfers of dead debris. Here, we have reviewed how macrophages regulate development, maintain homeostasis and influence repair and regeneration. These emerging revelations should alter the way immunologists approach their studies. Indeed, many of the receptors, ligands and pathways that immunologists study are used by immune cells to perform non-immune functions. Perhaps the

Glossary

Anastomosis
the fusion of two distinct entities, often used when referring to blood vessels.
Atherosclerotic plaques
cholesterol-rich deposits inside the wall of arteries that can obstruct blood flow or rupture and cause clot formation.
Auditory and visual evoked potentials
chemical detection of neural activities that occur in response to audio of visual stimulation.
CD11b-DTR transgenic mice
mice that have been genetically engineered to express the simian diphtheria toxin receptor (DTR) in

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