Abstract
Indoleamine 2, 3-dioxygenase (IDO), an immunosuppressive enzyme that mediates the conversion of tryptophan to kynurenine, was shown to play a key role in placental development during normal pregnancy. However, little is known about the pattern of IDO expression in the endometrium and its attendant functional significance in pregnancies complicated with recurrent miscarriage (RM). Immunohistochemical studies of IDO, Foxp3, CD56, and CD163 expression were performed in endometrial samples from women with RM and healthy fertile controls. Our study found that IDO was localized in glandular epithelial cells, surface epithelial cells, and a small number of cells within the stromal compartment (including stromal cells and leukocytes) in endometrium. Indoleamine 2, 3-dioxygenase expression in the RM group was significantly lower than control group. The Foxp3 and CD56 expression were significantly increased with the elevated IDO expression in controls but not in RM. The percentage of Foxp3 + Tregs was significantly correlated with the level of IDO expression in the control group. Comparatively, no correlation was found between the percentage of CD56 + cells, CD163 + cells, and the level of IDO expression, no matter in controls and RM patients. This study demonstrated that the downregulation of IDO expression and noncoordinated association between IDO and other endometrial immune cells were associated with RM. Our findings provide insights into the contribution of IDO in immune regulation to maintain normal pregnancy, which could be used to develop potential therapeutic methods for RM.
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Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol. 2009;2(2):76–83.
Li TC, Makris M, Tomsu M, Tuckerman E, Laird S. Recurrent miscarriage: aetiology, management and prognosis. Hum Reprod Update. 2002;8(5):463–81.
Macklon NS, Brosens JJ. The human endometrium as a sensor of embryo quality. Biol Reprod. 2014;91(4):98.
Evans J, Salamonsen LA, Winship A, et al. Fertile ground: human endometrial programming and lessons in health and disease. Nat Rev Endocrinol. 2016;12(11):654–67.
Mekinian A, Cohen J, Kayem G, et al. Unexplained recurrent early miscarriages: Role of immunomodulation? Rev Med Interne. 2017;38(4):264–8.
Katz JB, Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev. 2008;222:206–21.
Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281(5380):1191–3.
Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4(10):762–74.
Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest. 2007;117(5):1147–54.
Ban Y, Chang Y, Dong B, Kong B, Qu X. Indoleamine 2,3-dioxygenase levels at the normal and recurrent spontaneous abortion fetal-maternal interface. J Int Med Res. 2013;41(4):1135–49.
Liu X, Liu Y, Ding M, Wang X. Reduced expression of indoleamine 2,3-dioxygenase participates in pathogenesis of preeclampsia via regulatory T cells. Mol Med Rep. 2011;4(1):53–8.
Badawy AA, Namboodiri AM, Moffett JR. The end of the road for the tryptophan depletion concept in pregnancy and infection. Clin Sci. 2016;130(15):1327–33.
Ebina Y, Shimada S, Deguchi M, Maesawa Y, Iijima N, Yamada H. Divergence of helper, cytotoxic, and regulatory T cells in the decidua from miscarriage. Am J Reprod Immunol. 2016;76(3):199–204.
Quan X, Yang X. Correlation between unexplained recurrent spontaneous abortion with CD4(+)CD25(+) regulatory T-cell and killer cell immunoglobulin-like receptor levels. Exp Ther Med. 2017;14(2):1459–62.
Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176(11):6752–61.
Sharma MD, Baban B, Chandler P, et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest. 2007;117(9):2570–82.
Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008;181(8):5396–404.
Manches O, Munn D, Fallahi A, et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest. 2008;118(10):3431–9.
van der Marel AP, Samsom JN, Greuter M, et al. Blockade of IDO inhibits nasal tolerance induction. J Immunol. 2007;179(2):894–900.
Matteoli G, Mazzini E, Iliev ID, et al. Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut. 2010;59(5):595–604.
Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10.
Della Chiesa M, Carlomagno S, Frumento G, et al. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood. 2006;108(13):4118–25.
Gaynor LM, Colucci F. Uterine natural killer cells: functional distinctions and influence on pregnancy in humans and mice. Front Immunol. 2017;8:467.
Kuon RJ, Weber M, Heger J, et al. Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am J Reprod Immunol. 2017;78(4):e12721.
Sato N, Saga Y, Mizukami H, et al. Downregulation of indoleamine-2,3-dioxygenase in cervical cancer cells suppresses tumor growth by promoting natural killer cell accumulation. Oncol Rep. 2012;28(5):1574–8.
Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196(4):459–68.
Mege JL, Mehraj V, Capo C. Macrophage polarization and bacterial infections. Curr Opin Infect Dis. 2011;24(3):230–4.
Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol. 2008;181(6):3733–9.
Gronlund J, Vitved L, Lausen M, Skjodt K, Holmskov U. Cloning of a novel scavenger receptor cysteine-rich type I transmembrane molecule (M160) expressed by human macrophages. J Immunol. 2000;165(11):6406–15.
Buechler C, Ritter M, Orso E, Langmann T, Klucken J, Schmitz G. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and anti-inflammatory stimuli. J Leukocyte Biol. 2000;67(1):97–103.
Komohara Y, Hirahara J, Horikawa T, et al. AM-3K, an antimacrophage antibody, recognizes CD163, a molecule associated with an anti-inflammatory macrophage phenotype. J Histochem Cytochem: official journal of the Histochemistry Society. 2006;54(7):763–71.
Wang XF, Wang HS, Wang H, et al. The role of indoleamine 2,3-dioxygenase (IDO) in immune tolerance: focus on macrophage polarization of THP-1 cells. Cell Immunol. 2014;289(1-2):42–8.
Iwahashi N, Yamamoto M, Nanjo S, Toujima S, Minami S, Ino K. Downregulation of indoleamine 2, 3-dioxygenase expression in the villous stromal endothelial cells of placentas with preeclampsia. J Reprod Immunol. 2017;119:54–60.
Sedlmayr P, Blaschitz A, Wintersteiger R, et al. Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. Mol Hum Reprod. 2002;8(4):385–91.
Ligam P, Manuelpillai U, Wallace EM, Walker D. Localisation of indoleamine 2,3-dioxygenase and kynurenine hydroxylase in the human placenta and decidua: implications for role of the kynurenine pathway in pregnancy. Placenta. 2005;26(6):498–504.
Sandra O, Mansouri-Attia N, Lea RG. Novel aspects of endometrial function: a biological sensor of embryo quality and driver of pregnancy success. Reprod Fertil Dev. 2011;24(1):68–79.
Chang RQ, Li DJ, Li MQ. The role of indoleamine-2,3-dioxygenase in normal and pathological pregnancies. Am J Reprod Immunol. 2017;79(4):e12786.
Kudo Y, Boyd CA, Spyropoulou I, et al. Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta. J Reprod Immunol. 2004;61(2):87–98.
Miwa N, Hayakawa S, Miyazaki S, et al. IDO expression on decidual and peripheral blood dendritic cells and monocytes/macrophages after treatment with CTLA-4 or interferon-gamma increase in normal pregnancy but decrease in spontaneous abortion. Mol Hum Reprod. 2005;11(12):865–70.
Diao LH, Li GG, Zhu YC, et al. Human chorionic gonadotropin potentially affects pregnancy outcome in women with recurrent implantation failure by regulating the homing preference of regulatory T cells. Am J Reprod Immunol. 2017;77(3):e12618.
Leavy O. Tolerance: induced T(Reg) cells evolved to protect the fetus. Nat Rev Immunol. 2012;12(8):554–5.
Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34(3):137–43.
Sundrud MS, Koralov SB, Feuerer M, et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science. 2009;324(5932):1334–8.
Keller TL, Zocco D, Sundrud MS, et al. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol. 2012;8(3):311–7.
Nguyen NT, Kimura A, Nakahama T, et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A. 2010;107(46):19961–6.
Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185(6):3190–8.
Chung DJ, Rossi M, Romano E, et al. Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood. 2009;114(3):555–63.
Russell P, Sacks G, Tremellen K, Gee A. The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure. III: further observations and reference ranges. Pathology. 2013;45(4):393–401.
Horowitz A, Strauss-Albee DM, Leipold M, et al. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. Sci Transl Med. 2013;5(208):208ra145.
Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.
Watkins SK, Egilmez NK, Suttles J, Stout RD. IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol. 2007;178(3):1357–62.
Tjiu JW, Chen JS, Shun CT, et al. Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Invest Dermatol. 2009;129(4):1016–25.
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Wei, H., Liu, S., Lian, R. et al. Abnormal Expression of Indoleamine 2, 3-Dioxygenase in Human Recurrent Miscarriage. Reprod. Sci. 27, 1656–1664 (2020). https://doi.org/10.1007/s43032-020-00196-5
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DOI: https://doi.org/10.1007/s43032-020-00196-5