Functional and phenotypic characteristics of classical (M1) and alternatively activated (M2) macropfages and their role during normal and pathological pregnancy (literature review)

Bogdanova I.M.; Boltovskaya M.N.

doi:https://doi.org/10.17116/repro201925051110

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Abstract:

Macrophages belong to the population of mononuclear phagocytes of the innate immune system and represent one of the main subclasses of leukocytes in decidua. Due to the high phenotypic plasticity, decidual macrophages perform various functions during pregnancy. The dominant subclass is M2 polarized macrophages featured by the immunosuppressive phenotype and involved in maintaining maternal immune tolerance to the semi-allogeneic fetus. In the early period of pregnancy, pro-angiogenic factors produced by macrophages are engaged in the remodeling of the uterine spiral arteries, ensuring the formation of adequate blood circulation in the uteroplacental zone. Under microbial infection activation of macrophages via Toll receptors occurs and their phenotypic switching to the M1 proinflammatory phenotype. Strict space-time control of the M1/M2 polarization in this zone is necessary for a successful pregnancy. Dysregulation can contribute to aberrant activation of macrophages and pregnancy pathologies, such as spontaneous abortions, premature birth, preeclampsia, fetal growth retardation and intrauterine infections. This review summarizes the current understanding of the biology of macrophages, its classification with special regard to phenotypic and functional characteristics of decidual macrophages in the uteroplacental zone during normal pregnancy and the potential involvement of abnormally activated macrophages in the pathology of pregnancy.

Keywords:

macrophages

polarization

pregnancy

Authors:

Bogdanova I.M.

Research Institute of Human Morphology of Ministry of Science and Higher Education of the Russia, Moscow, Russia

Boltovskaya M.N.

Research Institute of Human Morphology, Moscow, Russia

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References:

Yona S, Kim KW, Wolf Y, Mildner A,Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38(1):78-91. https://doi.org/10.1016/j.immuni.2012.12.001
Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nature Reviews Immunology. 2014;14(6):392-404. https://doi.org/10.1038/nri3671
Atri C, Guerfali FZ, Laouini D. Role of human macrophage polarization in inflammation during infectious diseases. International Journal of Molecular Sciences. 2018;19(6):E1801. https://doi.org/10.3390/ijms19061801
Sokolov DI, Selkov SA. Decidual macrophages: the role in immunologic dialogue of mother and fetus. Immunologiya. 2014;35(2):113-117. (In Russ.)
Ning F, Liu H, Lash GE. The role of decidual macrophages during normal and pathological pregnancy. American Journal of Reproductive Immunology. 2016;75(3):298-309. https://doi.org/10.1111/aji.12477
Faas MM, De Vos P. Innate immune cells in the placental bed in healthy pregnancy and preeclampsia. Placenta. 2018; 69;125-133. https://doi.org/10.1016/j.placenta.2018.04.012
Sica A, Erreni M, Allavena P, Porta C. Macrophage polarization in pathology. Cellular and Molecular Life Sciences. 2015;72(21):4111-4126. https://doi.org/10.1007/s00018-015-1995-y
Hume DA. Differentiatiom and heterogeneity in the mononuclear phagocyte system. Mucosal Immunology. 2008;1(6):432-441. https://doi.org/10.1038/mi.2008.36
Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodeling. Journal of Pathology. 2013;229(2):176-185. https://doi.org/10.002/path.4133
Das A, Sinha M, Datta S, Abas M, Chaffee S, Sen CK, Roy S. Monocyte and macrophage plasticity in tissue repair and regeneration. The American Journal of Pathology. 2015;185(10):2596-2606. https://doi.org/10.1016/j.ajpath.2015.06.001
Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014;41(1):21-35. https://doi.org/10.1016/j.immuni.2014
Davies LC, Taylor PR. Tissue-resident macrophages: then and now. Immunology. 2015;144(4):541-548. https://doi.org/10.1111/imm.12451
Gentek R, Molawi K, Sieweke MH. Tissue macrophage identity and self-renewal. Immunological Reviews. 2014;262(1):56-73. https://doi.org/10.1111/imr.12224
Hoeffel G, Ginhoux F. Fetal monocytes and the origins of tissue-resident macrophages. Cell Immunology. 2018;330;5-15. https://doi.org/10.1016/j.cellimm.2018.01.001
Zhao Y, Zou W, Du J, Zhao Y. The origins and homeostasis of monocytes and tissue-resident macrophages in physiological situation. Journal of Cellular Physiology. 2018;223(10):6425-6439. https://doi.org/10.1002/jcp.26461
Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, García-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M. Tissue-resident macrophages self-maintain locally throuhout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38(4):792-804. https://doi.org/10.1016/j.immuni.2013.04.004
Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity. 2014;41(5):694-707. https://doi.org/10.1016/j.immuni.2014.10.008
Bashir S, Sharma Y, Elahi A, Khan F. Macrophage polarization: the link between inflammation and related diseases. Inflammation Research. 2016;65(1):1-11.
Li C, Xu MM, WangK, Adler AJ, Vella AT, Zhou B. Macrophage polarization and meta-inflammation. Translational Research. 2018;191:29-44. https://doi.org/10.1016/j.trsl.2017.10.004
Saranda A, Do DC, Kumar S, Fu QL, Gao P. Macrophage polarization and allergic asthma. Translational Research. 2018;191:1-14. https://doi.org/10.1016/j.trsl.2017.09.002
Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Frontiers in Immunology. 2014;28 (5):614. https://doi.org/10.3389/fimmu.201400614
Murray PJ. Macrophage polarization. Annual Review of Physiology. 2017;10(79):541-566. https://doi.org/10.1146/annurev-physiol-022516-034339
Porta C, Riboldi E, Ippolito A, Sica A. Molecular and epigenetic basis of macrophage polarized activation. Seminars in Immunology. 2015;27(4):237-248. https://doi.org/10.1016/j.smim.2015.10.003
Nagamatsu T, Schust DJ. The immunomodulatory roles of macrophages at the maternal-fetal interface. Reproductive Sciences. 2010;17(3):2098-2218. https://doi.org/10.1177/1933719109349962
Martinez FO, Sica A,Mantovani A, Locati M. Macrophage activation and polarization. Frontiers in Bioscience. 2008;1(13):453-461.
De Paoli F, Staels B, Chinetti-Gbaguidi G. Macrophage phenotypes and their modulation in atheropsclerosis. Circulation Journal. 2014;78(8):1775-1781.
Chistiakov DA,Bobrishev YV, Nikiforov NG, Elizova NV, Dobenin IA, Orekhov AN. Macrophage phenotypic plasticity in atherosclerosis: The associated features and the peculiarities of the expression of inflammatory genes. International Journal of Cardiology. 2015;184:436-445. https://doi.org/10.1016/j.ijcard.2015.03.055
Tarigue AA, Logan J, Thomas E, Holt PG, Sly PD, Fantino E. Phenotipic, functional, and plasticity features of classical and alternatively activated human macrophages. American Journal of Respiratory Cell and Molecular Biology. 2015;53(5):676-688. https://doi.org/10.1165/rcmb.2015-0012OC
Mills CD. Macrophage arginin metabolism to ornitin/urea or nitric oxide/citrulline: life or death issue. Critical Reviews in Immunology. 2001;21(5):399-425. https://doi.org/10.1615/CritRevimmunol.v21.i5.10
Malyshev IYu. Epigenetic, post-transcriptional and metabolic mechanisms of macrophage reprogramming. Patologicheskaya fiziologiia i èksperimental’naya terapiya. 2015;3:118-127. (In Russ.)
Care AS, Diener KR, Jasper MJ, Brown HM, Ingman WV, Robertson SA. Macrophages regulate corpus luteum development during embryo implantation in mice. Journal of Clinical Investigation. 2013;123(8):3472-3487. https://doi.org/10.1172/JCI60651
Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Annals of the New York Academy of Sciences. 2011;1221:80-87. https://doi.org/10.1111/j.1749-6632.2010.05938.x
Vacca P, Cantoni C, Vitale M, Prato C, Canegallo F, Fenoglio D, Ragni N, Moretta L, Mingari MC. Crosstalk between decidual NK and CD14+ myelomonocytic cells result in induction of Tregs and immunosuppression. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(26):11918-11923. https://doi.org/10.1073/pnas.1001749107
Gustafsson C, Mjösberg J, Matussek A, Geffers R, Matthiesen L, Berg G, Sharma S, Buer J, Ernerudh J. Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. PLoS One. 2008;3(4):e2078. https://doi.org/10.1371/lournal.pone.0002078
Kim SY, Romero R, Tarca AL, Bhatti G, Kim CJ, Lee J, Elsey A, Than NG, Chaiworapongsa T, Hassan SS, Kang GH, Kim JS. Methylome of fetal and maternal monocytes and macrophages at the fetomaternal interface. American Journal of Reproductive Immunology. 2012;68(1):8-27. https://doi.org/10.1111/j.1600-0897.2012.01108.x
Repnik U, Tilburgs T, Roelen DL, van der Mast BJ, Kanhai HH, Scherjon S, Claas FH. Comparison of macrophage phenotype between deciduas basalis and deciduas parietalis by flow cytometry. Placenta. 2008;29(5):405-412. https://doi.org/10.1016/j.placenta.2008.02.004
Laskarin G, Cupurdija K, Tokmadzic VS, Dorcic D, Dupor J, Juretic K, Strbo N, Crncic TB, Marchezi F, Allavena P, Mantovani A, Randic Lj, Rukavina D. The presence of functional mannose receptor on macrophages at the maternal-fetal interface. Human Reproduction. 2005;20(4):1057-1066. https://doi.org/10.1093/humrep/deh740
Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL. Evidence for immune cell involvement in decidual spiral arteroile remodeling in early human pregnancy. The American Journal of Pathology. 2009;174(5):1959-1971. https://doi.org/10.2353/ajpath.2009.080995
Zhang YH, He M, Wang Y, Liao AH. Modulators of the balance between M1 and M2 macrophages during pregnancy. Frontiers in Immunology. 2017;8:120. https://doi.org/10.3389/fimmu.2017.00120
Vacca P, MontaldoE, Vitale C, Croxatto D, Morreta L, Mingari MC. MSC and innate immune cell interaction: a lesson from human decidua. Immunology Letters. 2015;168(2):170-174. https://doi.org/10.1016/jimlet.2015.05.006
Han G, Chen G, Shen B, Li Y. Tim-3: an activation marker and activation limiter of innate immune cells. Frontiers in Immunology. 2013;4:449. https://doi.org/10.3389./fimmu.2013.00449
Chabtini L, Mfarrej B, Mounayar M, Zhu B, Batal I, Dakle PJ, Smith BD, Boenisch O, Najafian N, Akiba H, Yagita H, Guleria I. TIM-3 regulates innate immune cells to induce fetomaternal tolerance. Journal of Immunology. 2013;190(1):88-96. https://doi.org/10.4049/jimmunol.1202176
Jaiswal MK, Mallers TM, Larsen B, Kwak-Kim J, Chaouat G, Gilman-Sachs A, Beaman KD. V-ATPase upregulation during early pregnancy: a possible link to establishmwent of an inflammatory response during preimplantation period of pregnancy. Reproduction. 2012;143(5):713-725. https://doi.org/10.1530/REP-12-0036
Shynlova O, Tsui P, Dorogin A, Lye SJ. Monocyte chemoattractant protein-1 (CCL-2) integrates mechanical and endocrine signals that mediate term and preterm labor. Journal of Immunology. 2008;181(2):1470-1479. https://doi.org/10.4049/jimmunol.181.2.1470
Osman I, Young A, Ledingham MA, Thomson AJ, Jordan F, Greer IA, Norman JE. Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. Molecular Human Reproduction. 2003;9(1):445-449. https://doi.org/10.1093/molehr/gag001
Brown MB, von Chamier M, Allam AB, Reyes L. M1/M2 macrophage polarity in normal and complicated pregnancy. Frontiers in Immunology. 2014;5:606. https://doi.org/10.3389/fimmu.2014.00606
Tsao FY, Wu MY, Chang YL, Wu CT, Ho HN. M1 macrophages decrease in the deciduae from normal pregnancies but not from spontaneous abortions or unexplained recurrent spontaneous abortions. Journal of the Formosan Medical Association. 2017;117:204-211. https://doi.org/10.1016/j.jfma.2017.03.011
Khoperskaya OV, En’kova EV, Atyakshin DA. Assessment of decidual macrophages population in patients with non-developin gpregnancy. Zhurnal anatomii i gistopatologii. 2018;7(3):75-80. (In Russ.) https://doi.org/10.18499/2225-7357-2018-7-3-75-80
Yao Y, Xu X-H, Jin L. Macrophage Polarization in Physiological and Pathological Pregnancy. Frontiers in Immunology. 2019;10:792. https://doi.org/10.3389/fimmu.2019.00792
Reister F, Frank HG, Kingdom JC, Heyl W, Kaufmann P, Rath W, Huppertz B. Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women. Laboratory Investigation. 2001;81(8):1143-1152.
Lash GE, Otun HA, Innes BA, Bulmer JN, Searle RF, Robson SC. Inhibition of trophoblast cell invasion by TGFB1, 2, and 3 is associated with a decrease in active proteases. Biology of Reproduction. 2005;73(2):374-381.
Mor G, Abrahams VM. Potential role of macrophages as immunoregulators of pregnancy. Reproductive Biology and Endocrinology. 2003;1:119-127.
Straszewski-Chavez SL, Abrahams VM, Mor G. The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocrine Reviews. 2005;26(7):877-897.
Minas V, Jeschke U, Kalantaridou SN, Richter DU, Reimer T, Mylonas I, Friese K, Makrigiannakis A. Abortion is associated with increased expression of FasL in decidual leukocytes and apoptosis of extravillous trophoblasts: a role for CRH and urocortin. Molecular Human Reproduction. 2007;13(9):663-673.