Macrophages have long been considered to be important immune effector cells. Élie Metchnikoff, who won the Nobel Prize 100 years ago for his description of phagocytosis, proposed that the key to immunity was to “stimulate the phagocytes”(REF. 1
). Since this discovery, immunologists have been occupied with the concept of macrophages as immune effector cells and with understanding how these cells participate in host defence. However, by focusing on the immune functions of macrophages, immunologists have ignored their vital homeostatic roles, which are independent of their involvement in immune responses.
Macrophages are prodigious phagocytic cells that clear approximately 2 × 1011
erythrocytes each day; this equates to almost 3 kg of iron and haemoglobin per year that is ‘recycled’ for the host to reuse. This clearance process is a vital metabolic contribution without which the host would not survive. Macrophages are also involved in the removal of cellular debris that is generated during tissue remodelling, and rapidly and efficiently clear cells that have undergone apoptosis. These processes occur independently of immune-cell signalling, and the removal of ‘effete’ or apoptotic cells seems to result in little or no production of immune mediators by unstimulated macrophages2
. The receptors that mediate these homeostatic clearance processes include scavenger receptors, phosphatidyl serine receptors, the thrombospondin receptor, integrins and complement receptors3
. In general, these receptors that mediate phagocytosis either fail to transduce signals that induce cytokine-gene transcription or actively produce inhibitory signals and/or cytokines, and most of the phagocytosis that occurs on a daily basis by macrophages is independent of other immune cells. Therefore, the primary role of macrophages is not to function an elite immune effector cell, but instead as a common ‘janitorial’ cell, the main function of which is to clear the interstitial environment of extraneous cellular material.
Necrosis that results from trauma or stress also generates cellular debris that must be cleared by macrophages. In contrast to the examples cited above, the clearance of this debris markedly alters the physiology of macrophages. In many cases the debris from necrosis is loaded with endogenous danger signals, such as heat-shock proteins, nuclear proteins (including HMGB1; high-mobility group box 1
protein), histones, DNA and other nucleotides, and components of the extracellular matrix that are cleaved by cellular proteases4
. Phagocytosis of these components by macrophages leads to dramatic changes in their physiology, including alterations in the expression of surface proteins and the production of cytokines and pro-inflammatory mediators. The alterations in macrophage surface-protein expression in response to these stimuli could potentially be used to identify biochemical markers that are unique to these altered cells.
Box 1 | T-helper-17-cell responses and macrophages
The cytokine environment that is generated by T helper 1 (TH
1) or TH
2 cells can have distinct effects on the physiology of macrophages. However, the contribution of TH
17-cell-associated cytokines to macrophage biology is unclear. Similarly to interferon-γ (IFNγ) and interleukin-4 (IL-4), IL-17 is produced by cells of both the innate and adaptive immune response. In addition to TH
17 cells, IL-17 can be rapidly produced by both γδ T cells and natural killer T (NKT) cells101
. In mice, TH
17 cells develop in the presence of transforming growth factor-β (TGFβ) and IL-6 (REFS 25
), whereas in humans it is thought that IL-1β and IL-6 are necessary103
. In both humans and mice, the cytokine IL-23 seems to be pivotal for the expansion of these cells24
. As all of these cytokines are produced by macrophages, it is clear that these immune cells can influence TH
17-cell development (). however, in the gut lamina propria macrophages can inhibit IL-17 production and instead give rise to regulatory T cells104
The effect of IL-17 on macrophage physiology remains somewhat conjectural. There is some evidence that IL-17 can directly affect macrophage physiology. An early report105
suggested that IL-17 induced the production of pro-inflammatory cytokines by macrophages, but these studies have yet to be confirmed by careful quantitative analysis. It was recently shown that TH
17 cells could drive osteoclastogenesis from monocyte precursor cells and confer bone-resorption properties to these cells106
. Therefore, the interplay between TH
17 cells and macrophages can be complex, and the cytokines that are produced by macrophages (or dendritic cells) can either induce or inhibit the differentiation of TH
17 cells. In turn, the cytokines that are produced by TH
17 cells can influence osteoclast physiology. however, there is little evidence suggesting that IL-17 directly alters the physiology of most tissue macrophages, especially when compared with the evidence showing that TH
17 cells influence the migration and function of polymorphonuclear leukocytes.
Macrophages detect the endogenous danger signals that are present in the debris of necrotic cells through Toll-like receptors (TLRs)2
, intracellular pattern-recognition receptors and the interleukin-1 receptor (IL-1R), most of which signal through the adaptor molecule myeloid differentiation primary-response gene 88 (MyD88
. This function makes macrophages one of the primary sensors of danger in the host. Importantly, the stimulation of macrophages by cellular debris can occur in experimental animals that are devoid of lymphocytes, which confirms that these processes do not depend on adaptive immune responses2
The response of macrophages to endogenous danger signals is only one example of the many different stimuli that trigger macrophage activation in tissues. Macrophages have remarkable plasticity that allows them to efficiently respond to environmental signals and change their phenotype, and their physiology can be markedly altered by both innate and adaptive immune responses. Indeed, since the work of Mackaness in the 1970s7
we have learned that changes in the physiology of macrophages in response to some environmental signals can provide them with enhanced antimicrobial activity. However, environmental signals do not always induce changes that increase macrophage immune function. In fact, both innate and adaptive immune responses can give rise to macrophages that are more susceptible to pathogenic infections and less equipped to produce cytokines that enhance the immune response.
In an effort to emulate the T-cell literature, macrophages have been classified along what could be viewed as a linear scale, on which M1 macrophages represent one extreme and M2 macrophages represent the other (). In this classification, the M1 designation was reserved for classically activated macrophages and the M2 designation for alternatively activated macrophages8
. However, the M2 designation has rapidly expanded to include essentially all other types of macrophage9
. This classification persists despite a growing body of evidence indicating that the M2 designation encompasses cells with dramatic differences in their biochemistry and physiology10
. We suggest that a more informative foundation for macrophage classification should be based on the fundamental macrophage functions that are involved in maintaining homeostasis. We propose three such functions: host defence, wound healing and immune regulation. classifying macrophages according to these functions provides three basic macrophage populations, analogous to the three primary colours in a colour wheel (). This classification also helps to illustrate how macrophages can evolve to exhibit characteristics that are shared by more than one macrophage population, analogous to secondary colours in a colour wheel. Furthermore, it brings the classically activated (or host defence) macrophages closer to the other two cell types, allowing for the development of macrophages that share characteristics of two populations. In fact, we think that there may be many different shades of activation that have yet to be identified, resulting in a ‘spectrum’ of macrophage populations based on their function.
Colour wheel of macrophage activation
In this Review we describe some of the physiological alterations that occur in macrophages in response to environmental cues, and the mechanisms by which these changes can be exploited by pathogens or pathological processes to the detriment of the host. In addition, we discuss how the characterization and manipulation of specific macrophage populations can be used for therapeutic purposes.