Trophic macrophages in development and disease

Key Points

  • Cells of the mononuclear phagocytic lineage differentiate into many different types of macrophage with a wide range of activities. These include specialized types of macrophage, such as Kupffer cells in the liver, microglial cells in the brain, dendritic cells and the highly specialized bone osteoclasts.

  • Macrophages have many functions, including roles in immunity, apoptotic-cell clearance, wound healing and, as discussed in this Review, development.

  • Analysis of macrophage-deficient mice has revealed many functions for these cells in development, and their loss perturbs the morphology and physiology of many tissues, such as the brain, mammary glands and bones.

  • Macrophages promote epithelial-cell outgrowth and branching morphogenesis in several tissues, including the pancreas and the mammary glands.

  • Macrophages regulate angiogenesis during development, wound repair and disease.

  • Macrophages have a role in adipogenesis and obesity.

  • Macrophages are strongly involved in many chronic diseases that are associated with ageing and provide trophic factors that are similar to those used during development; this has the effect of increasing disease pathology.

  • Cancers sequester the developmental roles of macrophages to enhance their growth, invasive capacity, intravasation, progression and metastatic capacity.

Abstract

Specialized phagocytes are found in the most primitive multicellular organisms. Their roles in homeostasis and in distinguishing self from non-self have evolved with the complexity of organisms and their immune systems. Equally important, but often overlooked, are the roles of macrophages in tissue development. As discussed in this Review, these include functions in branching morphogenesis, neuronal patterning, angiogenesis, bone morphogenesis and the generation of adipose tissue. In each case, macrophage depletion impairs the formation of the tissue and compromises its function. I argue that in several diseases, the unrestrained acquisition of these developmental macrophage functions exacerbates pathology. For example, macrophages enhance tumour progression and metastasis by affecting tumour-cell migration and invasion, as well as angiogenesis.

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Figure 1: The mononuclear phagocytic lineage and the control of its development by growth factors.
Figure 2: The trophic role of macrophages in bone morphogenesis.
Figure 3: The trophic role of macrophages in ductal branching.
Figure 4: The trophic role of macrophages in neuronal patterning.
Figure 5: The trophic role of macrophages in angiogenesis and vascular remodelling.

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Acknowledgements

I apologize to all authors whose work I could not cite because of space restrictions. J.W.P. is the Louis Goldstein Swan Chair in Women's Cancer Research. His research discussed in this Review is supported by National Institutes of Health grants HD30820, CA131270, CA100324 and the Cancer Center (CA P30-13,330). I thank R. Hynes, Koch Integrative Cancer Center, Massachusetts Institute of Technology, Boston, and C. Stewart, Institute of Molecular Biology, Singapore, for their hospitality towards me during my sabbatical, a period during which this article was written.

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Glossary

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An angiogenic assay that depends on vascular sprouting from small rings of aorta cultured ex vivo.

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A type of fat involved in thermogenesis, so called because of the large number of mitochondria that give it its brown colour.

Polyoma middle T (PyMT) mouse model

A transgenic mouse model of breast cancer. The cancer is caused by the restricted expression of the polyoma middle T oncoprotein by mammary epithelial cells, which is under the control of the mouse mammary tumour virus promoter. This model is highly metastatic and recapitulates much of what is seen in human cancers.

Angiogenic switch

The marked increase in vascularization that is observed as benign tumours transition to malignancy.

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Pollard, J. Trophic macrophages in development and disease. Nat Rev Immunol 9, 259–270 (2009). https://doi.org/10.1038/nri2528

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