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Three macrophage subsets are identified in the uterus during early human pregnancy

Cellular & Molecular Immunology volume 15, pages 1027–1037 (2018)Cite this article

Abstract

Macrophages are crucial for a successful pregnancy, and malfunctions of decidual macrophages correlate with adverse pregnancy outcomes, such as spontaneous abortion and preeclampsia. Previously, decidual macrophages were often thought to be a single population. In the present study, we identified three decidual macrophage subsets, CCR2−CD11cLO (CD11clow, ~80%), CCR2−CD11cHI (CD11chigh, ~5%), and CCR2+CD11cHI (CD11chigh, 10–15%), during the first trimester of human pregnancy by flow cytometry analysis. CCR2−CD11cLO macrophages are widely distributed in the decidua, while CCR2−CD11cHI and CCR2+CD11cHI macrophages are primarily detected close to extravillous trophoblast cells according to immunofluorescence staining. According to RNA sequencing bioinformatics analysis and in vitro functional studies, these three subsets of macrophages have different phagocytic capacities. CCR2+CD11cHI macrophages have pro-inflammatory characteristics, while the CCR2−CD11cHI population is suggested to be anti-oxidative and anti-inflammatory due to its high expression of critical heme metabolism-related genes, suggesting that these two subsets of macrophages maintain an inflammatory balance at the leading edge of trophoblast invasion to facilitate the clearance of pathogen infection as well as maintain the homeostasis of the maternal-fetal interface. The present study physiologically identifies three decidual macrophage subsets. Further clarification of the functions of these subsets will improve our understanding of maternal-fetal crosstalk in the maintenance of a healthy pregnancy.

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Fig. 1: Identification of three distinct subsets of macrophages at the maternal–fetal interface during the first trimester of human pregnancy.
Fig. 2: Localization of the three macrophage subsets at the maternal–fetal interface.
Fig. 3: RNA-Seq analysis of the three decidual macrophage subsets.
Fig. 4: Phagocytic capacity of the three decidual macrophage subsets.
Fig. 5: CCR2+CD11cHI macrophages are pro-inflammatory.
Fig. 6: CCR2−CD11cHI macrophages expressed the highest levels of heme metabolism-related genes.
Fig. 7: A proposed model for the distribution and major functions of the three macrophage subsets at the maternal–fetal interface during early human pregnancy.

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Acknowledgements

We thank Xili Zhu and Shiwen Li for confocal image capture, Hua Qin for FACS, Can Peng and Lei Sun for TEM, and Tingting Wu for the phagocytosis experiment. We thank Meijing Wang, Rong Jing, and Jinglei Zhai for collecting samples from the hospital, and we thank Yong Zhao, Jingpian Peng, Yanling Wang, and Jay. C. Cross for discussion. This study was supported by grants from the National Natural Science Foundation of China (81490741 and 81401224) and the Ministry of Science and Technology of the People’s Republic of China (2016YFC1000208 and 2017YFC1001401).

Authors’ contributions

X.J. performed the experiments. H.W. and X.J. designed the study and interpreted the data. M.L. collected samples from the hospital. X.J. wrote the original manuscript. M.R.D. and H.W. modified the manuscript.

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Authors and Affiliations

  1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China

    Xiangxiang Jiang & Hongmei Wang

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Xiangxiang Jiang

  3. Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, 200011, China

    Mei-Rong Du

  4. Department of Obstetrics and Gynecology, Navy General Hospital of the Chinese PLA, Beijing, 100048, China

    Min Li

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Correspondence to Hongmei Wang.

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Jiang, X., Du, MR., Li, M. et al. Three macrophage subsets are identified in the uterus during early human pregnancy. Cell Mol Immunol 15, 1027–1037 (2018). https://doi.org/10.1038/s41423-018-0008-0

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