Regulatory macrophages (Mregs) represent one of basic macrophage population according fundamental macrophage function. These functions are host defense (classically activated macrophages), wound healing (alternatively activated/wound-healing macrophages) and immune regulation (Mregs). 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 (IL-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.
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. Coculuration of macrophages and regulatory T cells (Tregs) elicited differentiation of macrophages toward Mregs. 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 (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.
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 (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).
- Mosser, DM; Edwards, JP (Dec 2008). "Exploring the full spectrum of macrophage activation". Nature Reviews. Immunology. 8 (12): 958–69. doi:10.1038/nri2448. PMC 2724991. PMID 19029990.
- Gerber, JS; Mosser, DM (Jun 1, 2001). "Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors". Journal of Immunology. 166 (11): 6861–8. doi:10.4049/jimmunol.166.11.6861. PMID 11359846.
- Tiemessen, MM; Jagger, AL; Evans, HG; van Herwijnen, MJ; John, S; Taams, LS (Dec 4, 2007). "CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages". Proceedings of the National Academy of Sciences of the United States of America. 104 (49): 19446–51. doi:10.1073/pnas.0706832104. PMC 2148309. PMID 18042719.
- Wong, SC; Puaux, AL; Chittezhath, M; Shalova, I; Kajiji, TS; Wang, X; Abastado, JP; Lam, KP; Biswas, SK (Aug 2010). "Macrophage polarization to a unique phenotype driven by B cells". European Journal of Immunology. 40 (8): 2296–307. doi:10.1002/eji.200940288. PMID 20468007.
- Elenkov, IJ (Jun 2004). "Glucocorticoids and the Th1/Th2 balance". Annals of the New York Academy of Sciences. 1024: 138–46. doi:10.1196/annals.1321.010. PMID 15265778.
- Fleming, BD; Mosser, DM (Sep 2011). "Regulatory macrophages: setting the threshold for therapy". European Journal of Immunology. 41 (9): 2498–502. doi:10.1002/eji.201141717. PMC 4299459. PMID 21952805.
- Lucas, M; Zhang, X; Prasanna, V; Mosser, DM (Jul 1, 2005). "ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus". Journal of Immunology. 175 (1): 469–77. doi:10.4049/jimmunol.175.1.469. PMID 15972681.
- Edwards, JP; Zhang, X; Frauwirth, KA; Mosser, DM (Dec 2006). "Biochemical and functional characterization of three activated macrophage populations". Journal of Leukocyte Biology. 80 (6): 1298–307. doi:10.1189/jlb.0406249. PMC 2642590. PMID 16905575.
- Riquelme P, Haarer J, Kammler A, Walter L, Tomiuk S, Ahrens N, Wege AK, Goecze I, Zecher D, Banas B, Spang R, Fändrich F, Lutz MB, Sawitzki B, Schlitt HJ, Ochando J, Geissler EK, Hutchinson JA (2018). "TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity". Nature Communications. 9 (2858). doi:10.1038/s41467-018-05167-8. PMID 30030423.
- Riquelme P, Amodio G, Macedo C, Moreau A, Obermajer N, Brochhausen C, Ahrens N, Kekarainen T, Faendrich F, Cuturi C, Gregori S, Metes D, Schlitt HJ, Thomson AW, Geissler EK, Hutchinson JA, et al. (2017). "DHRS9 Is a Stable Marker of Human Regulatory Macrophages". Transplantation. 101 (11): 2731–38. doi:10.1097/TP.0000000000001814. PMID 28594751.