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Cell Mol Immunol. 2018 Dec;15(12):1010-1026. doi: 10.1038/s41423-018-0050-y. Epub 2018 Jun 15.

Relevance of placental type I interferon beta regulation for pregnancy success.

Author information

1
Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
2
Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.
3
Department of Obstetrics, Gynecology & Reproductive Biology, College of Human Medicine, Michigan State University, 400 Monroe Avenue NE, Grand Rapids, MI, 49503, USA.
4
Department of Pulmonary, Shanghai Children's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
5
Division of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
6
Perinatal Research Branch, NICHD/NIH, Detroit, MI, USA.
7
Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA. gil.mor@yale.edu.

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.

KEYWORDS:

ISGs; Interferon beta; TAM receptors; cytokine; immune regulation; trophoblast; type I interferon

PMID:
29907882
PMCID:
PMC6269429
[Available on 2019-12-01]
DOI:
10.1038/s41423-018-0050-y

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