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Involvement of the Tim-3 Pathway in the Pathogenesis of Pre-Eclampsia

  • Reproductive Biology: Original Article
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Abstract

Current methods of early diagnosis and prevention of pre-eclampsia (PE) are limited; the only available definite treatment is the initiation of delivery and complete removal of the placenta. Inappropriate activation of the immune system is thought to play considerable roles in PE. T cell immunoglobulin mucin-3 (Tim-3) has been reported to regulate immune responses and play important roles in maternal-fetal tolerance during early pregnancy. In this study, we investigated the functional regulation of Tim-3 in the maternal-fetal crosstalk during 3rd-trimester healthy pregnancy and its possible role in the pathogenesis of PE. We found that Tim-3 expression on decidual immune cells was associated with production of anti-inflammatory cytokines. Tim-3 pathway blockade resulted in higher IFN-γ but lower IL-4 and IL-10 production. Using a tube formation assay between HTR8/SVneo cells and human umbilical vein endothelial cells, we found that Tim-3 pathway blockade inhibits tube formation and reversed by addition of recombinant IL-4 and/or IL-10. Pre-eclamptic patients showed reduced Tim-3 expression on both decidual and peripheral immune cells (especially on peripheral CD8+T cells). Therefore, we proposed that abnormal Tim-3 signal resulted in immunological imbalance at the maternal-fetal interface and may be involved in the progress of PE by affecting uterine spiral artery remodeling. Our study expanded the regulatory function of Tim-3 signaling pathway to the 3rd-trimester pregnancy and provided a new target for early warning and therapeutic strategies of PE.

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Acknowledgements

This work was supported by grant from the Nature Science Foundation from National Nature Science Foundation of China (NSFC) (31700799, 31970859, 81601311, 81630036), the National Key R&D Program of China (2016YFC1000403 and 2017YFC1001403), the Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine (FIRMX2005XX), the Innovation oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation (CX2017 2), the Shanghai Sailing Program (17YF1411600), the Training Program for Young Talents of Shanghai Health System (2018YQ07), the Shanghai Chenguang Program (18CG09), and Development Fund of Shanghai Talents (2018110).

Funding

This work was supported by grant from the Nature Science Foundation from National Nature Science Foundation of China (NSFC) (31700799, 31970859, 81601311, 81630036), the National Key R&D Program of China (2016YFC1000403 and 2017YFC1001403), the Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine (FIRMX2005XX), the Innovation oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation (CX2017 2), the Shanghai Sailing Program (17YF1411600), the Training Program for Young Talents of Shanghai Health System (2018YQ07), the Shanghai Chenguang Program (18CG09), and Development Fund of Shanghai Talents (2018110).

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  1. Songcun Wang and Chunqin Chen contributed equally to this work.

Authors and Affiliations

  1. Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China

    Songcun Wang, Chunqin Chen, Fengrun Sun, Mengdie Li, Meirong Du, Xiaotian Li & Ying Zhang

  2. The Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China

    Songcun Wang, Chunqin Chen, Fengrun Sun, Mengdie Li, Meirong Du, Xiaotian Li & Ying Zhang

  3. Institutes of Biochemical Sciences, Fudan University, Shanghai, China

    Xiaotian Li

  4. The Shanghai Key Laboratory of Birth Defects, Shanghai, China

    Xiaotian Li

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  1. Songcun Wang
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Contributions

YZ and XTL conceived the experiments. SCW and CQC carried out the experiments and analyzed data. YZ, CQC, MDL, and FRS coordinated the sample collection, data interpretation, literature search, and figure preparation. SCW drafted the manuscript. YZ and MRD revised the manuscript. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Xiaotian Li or Ying Zhang.

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The study was approved by the institutional ethics board in Obstetrics and Gynecology Hospital of Fudan University, and each patient finished written consent.

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The authors declare that there are no conflicts of interest.

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Wang, S., Chen, C., Sun, F. et al. Involvement of the Tim-3 Pathway in the Pathogenesis of Pre-Eclampsia. Reprod. Sci. 28, 3331–3340 (2021). https://doi.org/10.1007/s43032-021-00675-3

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