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Relevance of placental type I interferon beta regulation for pregnancy success

Cellular & Molecular Immunology volume 15, pages 1010–1026 (2018)Cite this article

Abstract

Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paternal antigens. Dysregulation of inflammatory pathways in the placenta triggered by pathogens is one of the main factors responsible for pregnancy complications. Type I IFNs are key molecules modulating immune responses at the level of the placenta and are crucial for protection of the pregnancy via their antiviral and immune modulatory properties. In this study, we elucidate the mechanisms controlling the basal expression of IFNβ and its negative feedback. Using in vitro and in vivo animal models, we found that TLR signaling maintains basal IFNβ levels through the TLR4-MyD88-independent TBK/IRF3 signaling pathway. We describe the role of the TAM receptor Axl in the regulation of IFNβ function in human and mouse trophoblast cells. The absence of TAM receptors in vivo is associated with fetal demise due to dysregulation of IFNβ expression and its pro-apoptotic downstream effectors. Collectively, our data describe a feedback signaling pathway controlling the expression and function of IFNβ in the trophoblast that is essential for an effective response during viral and microbial infections.

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Acknowledgements

This study is in part funded by grants P01HD054713, R56AI124356, and 3N01 HD23342 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. We extend our gratitude to Dr. Ayesha Alvero for careful editing of this manuscript and Dr. Carla V Rothlin for help with TAM receptor KO animals. The authors would like to thank Dong-Su Jang, MFA (Medical Illustrator, Medical Research Supporting Section, Yonsei University College of Medicine, Seoul, Korea) for help with the illustrations.

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Authors and Affiliations

  1. Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA

    Ja-Young Kwon, Paulomi Aldo, Yuan You, Jiahui Ding, Karen Racicot, John Murphy, Guy Glukshtad, Michelle Silasi, Vikki M. Abrahams & Gil Mor

  2. Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University College of Medicine, Seoul, Korea

    Ja-Young Kwon

  3. Department of Obstetrics, Gynecology & Reproductive Biology, College of Human Medicine, Michigan State University, 400 Monroe Avenue NE, Grand Rapids, MI, 49503, USA

    Karen Racicot

  4. Department of Pulmonary, Shanghai Children’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Xiaoyan Dong

  5. Division of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Jian Peng & Li Wen

  6. Perinatal Research Branch, NICHD/NIH, Detroit, MI, USA

    Roberto Romero

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  1. Ja-Young Kwon
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Contributions

J.Y.K., P.A., and K.R. conceived and performed experiments, analyzed data, and wrote the manuscript. Y.Y., J.D., X.D., J.M., G.G., and J.P. performed the experiments, V.A., M.S., L.W., and R.R. analyzed the data. GM conceived the project, analyzed the data, wrote the manuscript, and provided supervision.

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Correspondence to Gil Mor.

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Kwon, JY., Aldo, P., You, Y. et al. Relevance of placental type I interferon beta regulation for pregnancy success. Cell Mol Immunol 15, 1010–1026 (2018). https://doi.org/10.1038/s41423-018-0050-y

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