Macrophages exhibit remarkable plasticity, which allows them to change their physiology in response to various different environmental stimuli.
The physiological characterization of each of these different macrophage populations may help to explain disease aetiologies.
The identification of biochemical markers that are specific for each of these macrophage populations may allow us to delete specific populations of macrophages, or to diagnose disease progression or resolution by the presence or absence of these populations.
Three populations of activated macrophages have been identified with unique characteristics. In addition, examples from disease states are given, in which macrophages share characteristics of more than one population. This provides a conceptual framework for a large number of different macrophage subpopulations based on this simple three-cell scaffold.
Some pathogens can exploit these changes in macrophage physiology and use macrophages for intracellular growth.
During disease progression, it is probable that macrophage populations will shift their phenotype, and this shift can contribute to disease resolution or progression.
Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities — host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.
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This work is supported in part by National Institutes of Health grants AI49388 and AI55576.
A common form of cell death (also known as programmed cell death) that can be caused by many physiological and developmental stimuli. Apoptosis involves cell shrinkage, chromatin condensation in the periphery of the nucleus, cell-membrane blebbing and DNA fragmentation into multiples of ∼180 base pairs. Eventually, the cell breaks up into many membrane-bound apoptotic bodies, which are phagocytosed by neighbouring cells.
A form of cell death that frequently results from toxic injury, hypoxia or stress. Necrosis involves the loss of cell integrity and the release of cell contents into the interstitium. This form of cell death usually occurs together with inflammation. Depending on the context, the self antigens that are released by necrotic cells could become immunogenic.
- Extracellular matrix
Secreted products of many cell types that form an organized scaffold for cell support.
- Classically activated macrophage
A macrophage that is activated through Toll-like receptors and interferon-γ. These cells exhibit enhanced killing of intracellular microorganisms, increased secretion of cytokines and mediators, and higher expression of co-stimulatory molecules.
- Alternatively activated macrophage
A macrophage that is activated by interleukin-4 (IL-4) or IL-13 and expresses arginase-1, mannose receptor (CD206) and IL-4 receptor-α. Pathogen-associated molecular patterns that are expressed by helminths may also drive the alternative activation of macrophages.
- Superoxide anions
Anions that are produced by NADPH oxidase in phagocytes and can dismutate to hydrogen peroxide, which can be converted into ferryl or hydroxyl radicals by the Fenton reaction.
A process whereby haematopoietic stem cells differentiate into multinucleated osteoclasts with bone-resorbing activity.
An enzyme that breaks down the glycosidic bonds in chitin.
An evolutionarily conserved process during which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation through fusion to secondary lysosomes.
- Hypothalamic–pituitary–adrenal axis
A major part of the neuroendocrine system, which controls reactions to stress and regulates digestion, energy use, sexuality and the immune system (generally through an immunosuppressive action).
A group of compounds that belongs to the corticosteroid family. These compounds can be naturally produced (hormones) or can be synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Some synthetic glucocorticoids (for example, dexamethasone) are used as chemotherapeutic drugs.
- Immune complexes
Antigen–antibody complexes that bind to and crosslink Fcγ receptors.
Lipid mediators that are derived from arachidonic acid through the cyclooxygenase pathway. Bergstrom, Samuelsson and Vane won the Nobel prize in Medicine in 1982 for showing that aspirin-like compounds could inhibit prostaglandin synthesis.
- G-protein-coupled receptor
A receptor that is composed of seven membrane-spanning helical segments, which are connected by extracellular and intracellular loops. These receptors associate with G proteins, which are a family of trimeric intracellular-signalling proteins that have specific β- and γ-chains, and one of several α-achains.
- Tumour-associated macrophage
A cell that differentiates from circulating blood monocytes that have infiltrated tumours. Tumour-associated macrophages constitute an important component of the tumour microenvironment and can have positive or negative effects on tumorigenesis (that is, tumour promotion or immunosurveillance, respectively).
- Antibody-dependent enhancement
A phenomenon that was originally described in Dengue virus infection in which the presence of antibody enhances viral infection and increases disease severity.
New growths or tumours, which can be either benign or malignant. Derived from the Greek for new formations.
The development of new blood vessels from existing ones. Angiogenesis is frequently associated with tumour development and metastasis.
- Adipose tissue
Loose connective tissue consisting primarily of adipocytes, the major function of which is to store energy in the form of fat.
- Insulin resistance
Failure of cells to appropriately respond to insulin-mediated induction of glucose uptake, resulting in increased blood sugar levels and possibly type 2 diabetes.
- Metabolic syndrome
A combination of disorders, including hypertension, obesity, high blood glucose levels and dyslipidaemia, that can result in cardiovascular disease.
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Mosser, D., Edwards, J. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8, 958–969 (2008). https://doi.org/10.1038/nri2448
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