To quote Alberto Mantovani: “Heterogenicity and plasticity are the hallmarks of cells belonging to the monocyte-macrophage lineage” (2,3). Monocytes leave the bone marrow, circulate to nearly every tissue, and then differentiate into macrophages: a process which is poorly understood (1,2,3). While our focus will be the variety of macrophage functional states, monocytes have functionality too! In fact, a subclass of IL-4aR+ monocytes are called “myeloid suppressor cells”, secrete IL-4 and IL-13, and can suppress the function of CD8+ cytotoxic T cells (2). Some human monocytes have even been observed to proliferate (8).
Once the monocyte enters into tissue, it becomes a macrophage with a functional activation state specific to the tissue as well as the local microenvironment (inflammation, infection, damage, age, etc.) (4,6). While the properties of tissue macrophages do “drift” with age, this has been shown to be caused by the tissue milieu and not due to any age-associated defect in the macrophages (4), and is reversible (6). Instead of an “on-off” switch, macrophage activation is a continuum: controlled not only by what cytokines are introduced (4), but also when (4,6). Macrophage function can also be continuously modified throughout the life of a cell, with IFN-γ stimulation exhibiting the most dramatic “resetting” (6). A “giant cell” is an extreme example of macrophage function, and also an exception to the general concept of macrophage plasticity (2,3). Giant cells are similar in appearance to osteoclasts (bone marrow macrophages) (6) in that they appear to be single cells with many (2-10+) nuclei, but are associated with granulomas formed by bacteria like M. tuberculosis (2,3). Although the specific function of these polynucleated macrophages is unknown, the formation process appears to be driven by CD44 and the nucleotide receptor P2X7, which is largely IL-4 associated (and thus M2: see below) (2,3).
The most common activation states of macrophages are “M1” and “M2”, mirroring the Th1 and Th2 nomenclature (3). M1 is referred to as “classical” activation, typically in response to bacterial infection or tissue damage, and can be induced by IFN-γ, LPS, TNF-α or GM-CSF (granulocyte/monocyte colony stimulating factor) (2,4). M1 macrophages are also referred to as “angry” due to their vastly increased iNOS levels, IL-1β, IL-6 and TNF-α production; they are both inducers and effectors of a Th1 response (2,3,6). Physiologically, M1 cells are effective against bacteria and intracellular parasites as well as tumors (2,3,8). M2 is unfortunately referred to as the “alternative” activation, i.e. every macrophage not expressing classical M1 functionality. M2 activation is typically induced by IL-4, IL-13, and IL-10 as well as glucocorticoids (2,4). M2 macrophages are largely considered to be pro-growth and anti-inflammatory, as they have increased arginase activity (in mouse, though not human, ref 8), increased scavenger receptor expression, increased secretion of IL-10 and TGF-β, and decreased expression of IL-1β (2,3,6). M2 cells promote the killing and encapsulation of parasites, tissue repair and remodeling, stimulation of a Th2 response (2,6,8), scarring (3), immunoregulation of T cell function (5), and are more recently associated with increasing tumor growth and progression (2,9). Phagocytosis can be performed by both M1 and M2 macrophages, and its complex regulation is beyond this brief summary. More specialized (and rare) macrophage phenotypes exist, such as either “M3” or “M4”, all depending upon different external stimuli (4).
In terms of human disease, high levels of IL-6 (M1 product) act to perpetuate chronic inflammation in the liver, leading to cancer (1). Interestingly, estrogens (acting through NF-κB) attenuate liver macrophage IL-6 production and induce an M2 phenotype, possibly explaining some of the gender discrepancy in liver cancer incidence (1). Similiarly, IL-1 can convert a steroid androgen receptor modulator (SARM) into a tumor-promoting transcription agonist (1). Inflammation resulting from head trauma can cause microglia (brain macrophages) to become M1, highly motile and neurotoxic (6). While it appears that M1 macrophages are associated with tissue damage and produce an environment favorable for tumor promotion, macrophages from tumor-bearing animals show an M2 phenotype (6,7,9), indicating that macrophages can be pathogenic regardless of activation state.
The story continues to evolve, with more work focusing on human macrophages as transcript analysis identifies significant expression differences between mouse and man (8). It is clear, however, that macrophage function is finely tuned by local stimuli, and is therefore entirely context dependent.
(1) Mantovani, A. Nature. 2007: 448(7153), pp 547-8
(2) Mantovani, A., et. al. Eur. J. Immunol. 2007: 37(1), pp14-16
(3) Mantovani, A., et. al. Immunity. 2005: 23(4), pp 344-6
(4) Stout, R.D. and Suttles, J., Immunol. Rev. 2005: 205, pp 60-71
(5) Nair, M.G., et. al. J. Immunol. 2006: 177(3), pp 1393-9
(6) Stout, R.D., et. al. J. Immunol. 2005: 175(1), pp 342-9
(7) Luo, Y., et. al. J. Clin. Invest. 2006: 116(8), pp 2132-41
(8) Martinez, F.O., et. al. J. Immunol. 2006: 177(10), pp 7303-11
(9) Redente, E.F., et al. Am. J. Pathol. 2007: 170(2), pp 693-708
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A word on microglia (brain macrophages)
As Fritz mentioned, microglia like their peripheral macrophage counterparts, can become activated upon head trauma or a whole host of other noxious stimuli (1). Microglia are considered the resident macrophages of the central nervous system (brain and spinal cord) given that they can become phagocytic when necessary. Yet resting microglia of an uninjured central nervous system are not likely engaged in phagocytic activity and are sometimes referred to more precisely as facultative phagocytes.
Don't let the nomenclature of a resting state give the idea of a static cell type. These cells have recently been imaged in the brains of anesthetized animals; importantly, in these studies the blood brain barrier remained intact and there was no central trauma. The time lapse videos obtained revealed that these little (micro) glia cells are constantly extending and retracting their processes (2). So the morphology is a bit different than peripheral macrophages; resting microglia have long, thin processes and found here are receptors for just about every signaling molecule, from neurotransmitters to cytokines and chemokines. Mild injuries may only cause microglia to become activated, but not phagocytic. More severe injuries, usually resulting in cell death, will cause microglia to become phagocytic at which point they take on a similar morphology of a peripherally activated macrophage (3). The end result, as originally stated in Fritz's blog, is entirely true in the central nervous system too: microglia activity is tuned to the local environment = context dependent.
1. Streit WJ. Progress in Neurobiol. 1999. 57: 563-581.
2. Davalos D et al. Nat Neurosci. 2005. 8(6): 752-758.
3. Wilson MA et al. Glia. 1994. 11: 18-34.
I thought your article was interesting, on point, and well-written. Thanks!
Nice! Glad you liked it.
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