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.
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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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.
- Reticuloendothelial system
A classification system, the functional definition of which is based on phagocytosis, that groups macrophages and endothelial cells together.
- Mononuclear phagocytic system
The current classification of macrophages, which is an ontological classification based on their bone marrow and monocyte origin.
- Definitive haematopoiesis
Haematopoiesis that results in the generation of all blood cell types.
A disease that is associated with the failure to remodel bone, resulting in occluded marrow cavities — literally, 'rock-like' bones.
- Growth plate
The area where osteoblasts initiate bone deposition and osteoclasts trigger bone remodelling.
- Liposome-encapsulated clodronate
Clodronate (dichloromethylene bisphosphonate) that is encapsulated in liposomes and that is taken up preferentially by macrophages through phagocytosis. The clodronate then kills the macrophages.
- Hypothalamic–pituitary–gonadal axis
The feedback system that regulates reproduction through the synthesis of sex steroid hormones in males and females. The highest level of control is in the hypothalamus, a region of the brain that secretes gonadotrophin-releasing hormone, which in turn stimulates the pituitary to produce gonadotrophins that act on the gonads to stimulate sex hormone synthesis.
- Visual evoked potential
A neuronal response to repeated visual cues.
- Retinal striate conductance
The pathway of neuronal impulses from the retina up the optic nerve to the striatum in the brain. The timing of this is a measure of neuronal conductance from a peripheral organ to the brain.
- Hyaloid vessel system
A vessel system that is laid down during the development of the eye and needs to be remodelled to allow unobstructed vision.
The process of stromal transformation in response to an invading embryo in the uterus. The transformed stroma protects and provides sustenance to the embryo and converts into a portion of the placenta as embryonic development proceeds.
- Aortic ring sprouting assay
An angiogenic assay that depends on vascular sprouting from small rings of aorta cultured ex vivo.
- Brown fat
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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