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Continuous activation of polymorphonuclear myeloid-derived suppressor cells during pregnancy is critical for fetal development

Abstract

The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy. Although studies have shown that myeloid-derived suppressor cells (MDSCs) play an important role in maintaining feto-maternal tolerance, little is known about the role of MDSCs in pregnancies with intrauterine growth retardation (IUGR). Here, we reported that the activation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) during pregnancy was closely associated with fetal growth. In humans, class E scavenger receptor 1 (SR-E1), a distinct marker for human PMN-MDSCs, was used to investigate PMN-MDSC function during pregnancy. Continuous activation of SR-E1+ PMN-MDSCs was observed in all stages of pregnancy, accompanied by high cellular levels of ROS and arginase-1 activity, mediated through STAT6 signaling. However, SR-E1+ PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity, lower arginase-1 activity and ROS levels, and decreased STAT6 phosphorylation level, which were accompanied by an increase in inflammatory factors, compared with those in normal pregnancies. Moreover, the population of SR-E1+ PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR. In mice, decreases in cell population, suppressive activity, target expression levels, and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies, which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice. Interestingly, the growth-promoting factors (GPFs) secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development. These findings collectively support that PMN-MDSCs have another new role in pregnancy, which can improve adverse neonatal outcomes.

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Acknowledgements

This work was supported by grants from the following institutions: the High-level Talent Start-up Funding of Southern Medical University, the National Natural Science Foundation of China (grant numbers: 31700061, 81971420 and 81991511), the Guangdong Special Support Program for Youth Science and Technology Innovation Talents (grant number: 2019TQ05Y585), the National Natural Science Foundation of Guangdong (grant number: 2019A1515011435), and the Science and Technology Program of Guangzhou (grant number: 201904010073).

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Y.H., L.W., and G.X. designed the study. M.S., Z.C., M.C., J.L., J.L., Z.X., X.Z., S.L., X.L., S.Z., S.F., and Y.L. performed the experiments in this study. Y.H., L.W., and G.X. wrote the paper. All authors contributed to the discussion of the study and revision of the paper.

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Correspondence to Gang Xiao or Liping Wang or Yumei He.

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Shi, M., Chen, Z., Chen, M. et al. Continuous activation of polymorphonuclear myeloid-derived suppressor cells during pregnancy is critical for fetal development. Cell Mol Immunol (2021). https://doi.org/10.1038/s41423-021-00704-w

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Keywords

  • Polymorphonuclear myeloid-derived suppressor cells
  • Class E scavenger receptor 1
  • Immunotolerance
  • Intrauterine growth retardation
  • Fetal development

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