Regulatory macrophages

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 (e. g. lipopolysaccharide or lipoteichoic acid) acting through Toll-like receptors. This stimulation specifically decreased IL-12 production and increased IL-10 production.[2] Coculture of macrophages with regulatory T cells (Tregs) caused differentiation of macrophages toward Mreg phenotype.[3] Similar effect provoked interaction of macrophages and B-1 B cells.[4] 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.[5]

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.[6] 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 (ERK, one of MAPK). Its activation combined with FcγR ligation mediates chromatin remodeling at the il-10 locus, to make the promoter more accessible to transcription factors.[7]

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 (CD86) 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 (SPHK1) and LIGHT (TNF superfamily 14).[8]