Regulatory macrophages represent one of basic macrophage population according fundamental macrophage function. These functions are host defense, wound healing and immune regulation. Physiological role of Mregs is to dampen the immune response and limit immunopathology. Unlike classically activated macrophages, Mregs produce high levels of anti-inflammatory cytokine interleukin 10 and turn off IL-12 synthesis. And unlike wound-healing macrophages, Mregs do not induct arginase, so they do not contribute to the production of the extracellular matrix.
Mreg origin
Mregs can arise following innate or adaptive immune responses. Mreg population was firstly described after FcγR ligation by IgG complexes in occurrence of pathogen-associated molecular patterns acting through Toll-like receptors. This stimulation specifically decreased IL-12 production and increased IL-10 production. Coculture of macrophages with regulatory T cellscaused differentiation of macrophages toward Mreg phenotype. Similar effect provoked interaction of macrophages and B-1 B cells. Mregs can even arise following stress responses. Activation of the hypothalamic-pituitary-adrenal axis leads to production of glucocorticoids that cause decreased production of IL-12 by macrophages.
Mechanism and regulation of IL-10 production
There are many different ways to prepare or generate Mregs, but there is necessary a combination of two stimuli to Mreg phenotypical switch and to appear sufficient production of high levels of IL-10. Nevertheless, a molecule mechanism that mediates their phenotypical change has not been identified yet. As a potential candidate it seems to be the extracellular signal regulated kinase. Its activation combined with FcγR ligation mediates chromatin remodeling at the il-10 locus, to make the promoter more accessible to transcription factors.
Biochemical and functional characterization of Mregs
Surprisingly, Mregs resemble classically activated macrophages more than alternatively activated macrophages. It means that biochemical differences between Mregs and classically activated macrophages are more subtle. Mregs produce high level of Il-10 and low levels of IL-12. They produce high levels of nitric oxide, but they almost do not have any arginase activity, so they can not produce urea. Mregs express high levels of co-stimulatory molecules and MHC Class II, they have the highest expression of these molecule in comparison with the other population of macrophages. T cells co-culture with Mregs showed intense activation and proliferation, so Mregs act as sufficient antigen-presenting cells. Nevertheless, in the secondary response these T cells produced high levels of IL-10. Mregs express two markers that might be used to identify Mregs in mouse, they are sphingosine kinase-1 and LIGHT.
