Regulatory Macrophages and the Maintenance of Homeostasis
Macrophages are a physiologically diverse collection of cells whose function can vary tremendously depending upon their anatomical location and the stimuli to which they are exposed. The plasticity of macrophages allows them to assume diametrically opposed physiologies and their ability to rapidly change their physiology in response to environmental cues permits these cells to be major mediators of homeostasis. On one hand macrophages can produce toxic mediators that can kill pathogens and promote immune responses. On the other, they can inhibit immune responses and orchestrate wound healing and tissue repair. The fact that macrophages with opposite physiologies can exist in an organism argues that a strategy to deplete macrophages would likely be ineffective, because it would deplete cells on both ends of the spectrum. In order to focus attention on the diverse roles of these cells, several investigators have attempted to assign names associated with given functional states, despite the fact that most acknowledge that these states can rapidly change. In fact, we once suggested that assigning a functional name to a rapidly changing population of macrophages was analogous to “assigning a color to a chameleon,” only to discover that no fewer than two other groups had previously made similar analogies. The assigning of names to macrophage populations based on their major activity, limitations notwithstanding, allows investigators to identify these cells in tissue or to direct drugs to specific subpopulations of macrophages in order to modulate immune responses. In this chapter we consider “regulatory macrophages” to be a broad general category of macrophages that are grouped by their functional activity. These activities include mitigating inflammation, regulating immune responses, and perhaps participating in tissue regeneration. We do not imply that all regulatory macrophages are identical. Rather, we propose that phenotypically diverse regulatory macrophages arise in response to a variety of exogenous and endogenous stimuli. We propose that all these regulatory macrophages share a common regulatory gene expression program leading to a reduced production of inflammatory mediators, and increased production of immunoregulatory cytokines and growth factors. We propose that these cells are major mediators of homeostasis and that without regulatory macrophages normal immune/inflammatory responses would invariably progress to immunopathology. Finally, we suggest that a part of the standard response of macrophages to inflammatory stimuli is the gradual transition from an inflammatory to a regulatory macrophage. This implies that macrophages can regulate their own physiology.
KeywordsMacrophage Population Regulatory Transcript Endotoxin Tolerance Regulatory Phenotype Regulatory Macrophage
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