Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neu5Gc regulates decidual macrophages leading to abnormal embryo implantation

Genes & Immunity volume 25, pages 149–157 (2024)Cite this article

Subjects

Abstract

Repeated implantation failure (RIF) is one of the most prominent problems in the field of assisted reproduction. Neu5Gc on the surface of decidual macrophages (dMΦ) leads to different activation patterns of dMΦ, which affects embryo implantation and development. Cmah−/− (Neu5Gc-deficient) mice induced to produce anti-Neu5Gc antibodies in vivo were given a special diet rich in Neu5Gc and their fertility was monitored. The long-term diet rich in Neu5Gc induced the decrease of endometrial receptivity of female mice. The pregnancy rate of female mice fed the normal diet was 63.6% (n = 11) and the average number of embryos was 9.571 ± 1.272, while the pregnancy rate of female mice fed the diet rich in Neu5Gc was 36.4% (n = 11) and the average number of embryos in pregnant mice was 5.750 ± 3.304. The intake of Neu5Gc and the production of anti-Neu5Gc antibody led to M1 polarization of endometrial dMΦ and abnormal embryo implantation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Accumulation of Neu5Gc and polarization of macrophages in endometrial tissue of RIF patients.
Fig. 2: Effects of free Neu5Gc on regulation of sialic acid metabolism and M1 polarization in THP-1 macrophages.
Fig. 3: Effect of anti-Neu5GC antibody on the polarization of decidual macrophages in mouse decidual tissue.
Fig. 4: Effects of dietary Neu5Gc intervention and anti-Neu5Gc antibody on pregnancy and morphological changes of decidual tissue in mice.

Similar content being viewed by others

Data availability

All data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Coughlan C, Yuan X, Nafee T, Yan J, Mariee N, Li TC. The clinical characteristics of women with recurrent implantation failure. J Obstet Gynaecol. 2013;33:494–8.

    Article  CAS  PubMed  Google Scholar 

  2. Chen X, Diao L, Lian R, Qi L, Yu S, Liu S, et al. Potential impact of maternal vitamin D status on peripheral blood and endometrium cellular immunity in women with recurrent implantation failure. Am J Reprod Immunol. 2020;84:e13243.

    Article  CAS  PubMed  Google Scholar 

  3. Zhuang B, Shang J, Yao Y. HLA-G: an important mediator of maternal–fetal immune-tolerance. Front Immunol. 2021;12:744324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Semmes EC, Coyne CB. Innate immune defenses at the maternal–fetal interface. Curr Opin Immunol. 2022;74:60–67.

    Article  CAS  PubMed  Google Scholar 

  5. Li Y, Zhang D, Xu L, Dong L, Zheng J, Lin Y, et al. Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models. Cell Mol Immunol. 2019;16:908–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sun F, Wang S, Du M. Functional regulation of decidual macrophages during pregnancy. J Reprod Immunol. 2021;143:103264.

    Article  CAS  PubMed  Google Scholar 

  7. Robertson SA, Care AS, Moldenhauer LM. Regulatory T cells in embryo implantation and the immune response to pregnancy. J Clin Investig. 2018;128:4224–35.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Meng YH, Zhou WJ, Jin LP, Liu LB, Chang KK, Mei J, et al. RANKL-mediated harmonious dialogue between fetus and mother guarantees smooth gestation by inducing decidual M2 macrophage polarization. Cell Death Dis. 2017;8:e3105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liao HQ, Han MT, Cheng W, Zhang C, Li H, Li MQ, et al. Decidual-derived RANKL facilitates macrophages accumulation and residence at the maternal–fetal interface in human early pregnancy. Am J Reprod Immunol. 2021;86:e13406.

    Article  CAS  PubMed  Google Scholar 

  10. Ono Y, Yoshino O, Hiraoka T, Sato E, Fukui Y, Ushijima A, et al. CD206+ M2-like macrophages are essential for successful implantation. Front Immunol. 2020;11:557184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Eastman AJ, Vrana EN, Grimaldo MT, Jones AD, Rogers LM, Alcendor DJ, et al. Cytotrophoblasts suppress macrophage-mediated inflammation through a contact-dependent mechanism. Am J Reprod Immunol. 2021;85:e13352.

    Article  CAS  PubMed  Google Scholar 

  12. Okerblom J, Varki A. Biochemical, cellular, physiological, and pathological consequences of human loss of N-glycolylneuraminic acid. ChemBioChem. 2017;18:1155–71.

    Article  CAS  PubMed  Google Scholar 

  13. Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, et al. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci USA. 1998;95:11751–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Irie A, Koyama S, Kozutsumi Y, Kawasaki T, Suzuki A. The molecular basis for the absence of N-glycolylneuraminic acid in humans. J Biol Chem. 1998;273:15866–71.

    Article  CAS  PubMed  Google Scholar 

  15. Martin MJ, Rayner JC, Gagneux P, Barnwell JW, Varki A. Evolution of human–chimpanzee differences in malaria susceptibility: relationship to human genetic loss of N-glycolylneuraminic acid. Proc Natl Acad Sci USA. 2005;102:12819–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kawanishi K, Dhar C, Do R, Varki N, Gordts PLSM, Varki A. Human species-specific loss of CMP-N-acetylneuraminic acid hydroxylase enhances atherosclerosis via intrinsic and extrinsic mechanisms. Proc Natl Acad Sci USA. 2019;116:16036–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Martin PT, Kawanishi K, Ashbrook A, Golden B, Samraj A, Crowe KE, et al. Serum antibodies to N-glycolylneuraminic acid are elevated in Duchenne muscular dystrophy and correlate with increased disease pathology in Cmah−/−mdx mice. Am J Pathol. 2021;191:1474–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Haller M, Yin Y, Ma L. Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility. Proc Natl Acad Sci USA. 2019;116:19541–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Angata T. Possible influences of endogenous and exogenous ligands on the evolution of human Siglecs. Front Immunol. 2018;9:2885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martin PT, Golden B, Okerblom J, Camboni M, Chandrasekharan K, Xu R, et al. A comparative study of N-glycolylneuraminic acid (Neu5Gc) and cytotoxic T cell (CT) carbohydrate expression in normal and dystrophin-deficient dog and human skeletal muscle. PLoS ONE. 2014;9:e88226.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Taylor RE, Gregg CJ, Padler-Karavani V, Ghaderi D, Yu H, Huang S, et al. Novel mechanism for the generation of human xeno-autoantibodies against the nonhuman sialic acid N-glycolylneuraminic acid. J Exp Med. 2010;207:1637–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ma F, Deng L, Secrest P, Shi L, Zhao J, Gagneux P. A mouse model for dietary xenosialitis: antibodies to xenoglycan can reduce fertility. J Biol Chem. 2016;291:18222–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kawanishi K, Coker JK, Grunddal KV, Dhar C, Hsiao J, Zengler K, et al. Dietary Neu5Ac intervention protects against atherosclerosis associated with human-like Neu5Gc loss—brief report. Arterioscler Thromb Vasc Biol. 2021;41:2730–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sroga JM, Wu DH, Ma F, Tecle E, Reynoso HS. Detection of the dietary xenoglycan N-glycolylneuraminic acid (Neu5Gc) and anti-Neu5Gc antibodies within reproductive tracts of male and female infertility subjects. Clin Obstet Gynecol Reprod Med. 2015;1:72–78.

    Article  Google Scholar 

  25. Altman MO, Gagneux P. Absence of Neu5Gc and presence of anti-Neu5Gc antibodies in humans—an evolutionary perspective. Front Immunol. 2019;10:789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Samraj AN, Pearce OM, Läubli H, Crittenden AN, Bergfeld AK, Banda K, et al. A red meat-derived glycan promotes inflammation and cancer progression. Proc Natl Acad Sci USA. 2015;112:542–7.

    Article  CAS  PubMed  Google Scholar 

  27. Alisson-Silva F, Kawanishi K, Varki A. Human risk of diseases associated with red meat intake: analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid. Mol Asp Med. 2016;51:16–30.

    Article  CAS  Google Scholar 

  28. Ghaderi D, Springer SA, Ma F, Cohen M, Secrest P, Taylor RE, et al. Sexual selection by female immunity against paternal antigens can fix loss of function alleles. Proc Natl Acad Sci USA. 2011;108:17743–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Läubli H, Varki A. Sialic acid–binding immunoglobulin-like lectins (Siglecs) detect self-associated molecular patterns to regulate immune responses. Cell Mol Life Sci. 2020;77:593–605.

    Article  PubMed  Google Scholar 

  30. Meyer SJ, Linder AT, Brandl C, Nitschke L. B cell Siglecs—news on signaling and its interplay with ligand binding. Front Immunol. 2018;9:2820.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by Siglecs. J Biol Chem. 2000;275:8633–40.

    Article  CAS  PubMed  Google Scholar 

  32. Duan S, Paulson JC. Siglecs as immune cell checkpoints in disease. Annu Rev Immunol. 2020;38:365–95.

    Article  CAS  PubMed  Google Scholar 

  33. Harris LK, Benagiano M, D’Elios MM, Brosens I, Benagiano G. Placental bed research: II. Functional and immunological investigations of the placental bed. Am J Obstet Gynecol. 2019;221:457–69.

    Article  CAS  PubMed  Google Scholar 

  34. Pérez S, Rius-Pérez S. Macrophage polarization and reprogramming in acute inflammation: a redox perspective. Antioxidants. 2022;11:1394.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yang D, Yang L, Cai J, Hu X, Li H, Zhang X, et al. A sweet spot for macrophages: focusing on polarization. Pharmacol Res. 2021;167:105576.

    Article  CAS  PubMed  Google Scholar 

  36. Zhao Y, Mahajan G, Kothapalli CR, Sun XL. Sialylation status and mechanical properties of THP-1 macrophages upon LPS stimulation. Biochem Biophys Res Commun. 2019;518:573–8.

    Article  CAS  PubMed  Google Scholar 

  37. Song Y, Pan Q, Xiao J, Li W, Ma H, Chen H, et al. Sialidase of Glaesserella parasuis augments inflammatory response via desialylation and abrogation of negative regulation of Siglec-5. Infect Immun. 2021;89:e00696-20.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhu H, Hou CC, Luo LF, Hu YJ, Yang WX. Endometrial stromal cells and decidualized stromal cells: origins, transformation and functions. Gene. 2014;551:1–14.

    Article  CAS  PubMed  Google Scholar 

  39. Bany BM, Hamilton GS. Assessment of permeability barriers to macromolecules in the rodent endometrium at the onset of implantation. Methods Mol Biol. 2011;763:83–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by National Natural Science Foundation of Fujian (2021J02036) and Medical Innovation in Fujian Province (2022CXA018). These funding sources played key supportive role for sample collection, molecular analysis of patient samples, and bioinformatics analysis.

Author information

Authors and Affiliations

  1. Center of Reproductive Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China

    Wu Yue, Zhou Huiling & Liu Yuxin

  2. Department of Pathology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China

    Wang Ling & Gao Feng

  3. Fujian Provincial Key Laboratory of Stem Cell Engineering and Regenerative Medicine, Fujian Medical University, China, Fuzhou

    Liu Qicai

Authors
  1. Wu Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhou Huiling
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liu Yuxin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wang Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gao Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liu Qicai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Q-CL and FG planned the project. Y-XL, H-LZ, LW, YW, and Q-CL conceived of and designed the study. Q-CL performed the sample collection. YW, FG, and Q-CL performed immunhistochemistry. Q-CL performed the expression analysis. All authors reviewed the manuscript and approved the final version.

Corresponding authors

Correspondence to Gao Feng or Liu Qicai.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All experimental procedures in animal work were approved by the Ethical Committee of Fujian Medical University. This study was carried out in accordance with the recommendations of Medical ethics committee of the First Affiliated Hospital of Fujian Medical University. The protocol was approved by the Medical ethics committee of the First Affiliated Hospital of Fujian Medical University [2023] 521.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yue, W., Huiling, Z., Yuxin, L. et al. Neu5Gc regulates decidual macrophages leading to abnormal embryo implantation. Genes Immun 25, 149–157 (2024). https://doi.org/10.1038/s41435-024-00268-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-024-00268-5

Search

Advanced search

Quick links