Relevance of placental type I interferon beta regulation for pregnancy success

Kwon, Ja Young; Aldo, Paulomi; You, Yuan; Ding, Jiahui; Racicot, Karen; Dong, Xiaoyan; Murphy, John F.; Glukshtad, Guy; Silasi, Michelle; Peng, Jian; Li, Wen; Abrahams, Vikki M.; Romero, Roberto; Mor, Gil

doi:10.1038/s41423-018-0050-y

Cited by 29 publications

(52 citation statements)

References 52 publications

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“…69,70 In addition to its antiviral role, IFN-has been reported to function as an immune modulator by limiting immune responses 71 and regulating the recruitment of immune cells. 30,72 The immune regulatory functions of IFN-are meditated by the expression of ISGs, which can promote apoptosis, 73 inhibit cell recruitment, 74 and induce cell differentiation. 75 PD-L1 belongs to the ISG family and is an important immune modulatory factor.…”

Section: Discussionmentioning

confidence: 99%

“…The primer sequences were previously described. 30 The amount of target relative to a calibrator was computed by 2 −∆∆CT , and the housekeeping gene -actin (ACTB) or GAPDH was used for normalization.…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

“…hypothesized that in the TEMs, TLR4 ligation by LPS preferentially would signal through the nonclassical TBK/IRF3 pathway because we did not observe a favored increase in NF-B-regulated proinflammatory cytokines. To test this hypothesis, TEMs and MDMs were treated with LPS (10 ng/ml) and samples were collected at15,30,60, 240, and 480 min posttreatment. We first determined the effect of LPS on the MyD88/NF B pathway by evaluating I Ba, an inhibitor of p65 nuclear translocation 44.…”

mentioning

confidence: 99%

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Trophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function

Zhang

Aldo

You

et al. 2020

Journal of Leukocyte Biology

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Decidual macrophages are in close contact with trophoblast cells during placenta development, and an appropriate crosstalk between these cellular compartments is crucial for the establishment and maintenance of a healthy pregnancy. During different phases of gestation, macrophages undergo dynamic changes to adjust to the different stages of fetal development. Trophoblast‐secreted factors are considered the main modulators responsible for macrophage differentiation and function. However, the phenotype of these macrophages induced by trophoblast‐secreted factors and the factors responsible for their polarization has not been elucidated. In this study, we characterized the phenotype and function of human trophoblast‐induced macrophages. Using in vitro models, we found that human trophoblast‐educated macrophages were CD14+CD206+CD86− and presented an unusual transcriptional profile in response to TLR4/LPS activation characterized by the expression of type I IFN‐β expression. IFN‐β further enhances the constitutive production of soluble programmed cell death ligand 1 (PD‐L1) from trophoblast cells. PD‐1 blockage inhibited trophoblast‐induced macrophage differentiation. Soluble PD‐L1 (sPD‐L1) was detected in the blood of pregnant women and increased throughout the gestation. Collectively, our data suggest the existence of a regulatory circuit at the maternal fetal interface wherein IFN‐β promotes sPD‐L1 expression/secretion by trophoblast cells, which can then initiate a PD‐L1/PD‐1‐mediated macrophage polarization toward an M2 phenotype, consequently decreasing inflammation. Macrophages then maintain the expression of sPD‐L1 by the trophoblasts through IFN‐β production induced through TLR4 ligation.

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Section: Discussionmentioning

confidence: 99%

Section: Quantitative Rt-pcrmentioning

confidence: 99%

mentioning

confidence: 99%

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Trophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function

Zhang

Aldo

You

et al. 2020

Journal of Leukocyte Biology

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“…A recent study has now focused on the temporal changes of TLRs expression taking place throughout gestation, which can help in devising an effective clinical diagnostic marker by observing the TLR pattern shifts at the materno-fetal interface during pregnancy (11). Another study elucidated the mechanism that regulates IFN-β expression in the trophoblast through a negative feedback loop to ensure an effective response against invading pathogens (47).…”

Section: Placentamentioning

confidence: 99%

Insight Into TLR4-Mediated Immunomodulation in Normal Pregnancy and Related Disorders

2020

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Unlike organ transplants where an immunosuppressive environment is required, a successful pregnancy involves an extremely robust, dynamic, and responsive maternal immune system to maintain the development of the fetus. A specific set of hormones and cytokines are associated with a particular stage of pregnancy. Any disturbance that alters this fine balance could compromise the development and function of the placenta. Although there are numerous underlying causes of pregnancy-related complications, untimely activation of Toll-like receptors (TLR), primarily TLR4, by intrauterine microbes poses the greatest risk. TLR4 is an important Pattern Recognition Receptor (PRR), which activates both innate and adaptive immune cells. TLR4 activation by LPS or DAMPs leads to the production of pro-inflammatory cytokines via the MyD88 dependent or independent pathway. Immune cells modulate the materno-fetal interface by TLR4-mediated cytokine production, which changes at different stages of pregnancy. In most pregnancy disorders, such as PTB, PE, or placental malaria, the TLR4 expression is upregulated in immune cells or in maternal derived cells, leading to the aberrant production of pro-inflammatory cytokines at the materno-fetal interface. Lack of functional TLR4 in mice has reduced the pro-inflammatory responses, leading to an improved pregnancy, which further strengthens the fact that abnormal TLR4 activation creates a hostile environment for the developing fetus. A recent study proposed that endothelial and perivascular stromal cells should interact with each other in order to maintain a homeostatic balance during TLR4-mediated inflammation. It has been reported that depleting immune cells or supplying anti-inflammatory cytokines can prevent PTB, PE, or fetal death. Blocking TLR4 signaling or its downstream molecule by inhibitors or antagonists has proven to improve pregnancy-related complications to some extent in clinical and animal models. To date, there has been a lack of knowledge regarding whether TLR4 accessories such as CD14 and MD-2 are important in pregnancy and whether these accessory molecules could be promising drug targets for combinatorial treatment of various pregnancy disorders. This review mainly focuses on the activation of TLR4 during pregnancy, its immunomodulatory functions, and the upcoming advancement in this field regarding the improvement of pregnancy-related issues by various therapeutic approaches.

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“…RNA was isolated from the samples using the Qiagen RNeasy Mini Kit (Qiagen, Waltham, MA). cDNA was prepared using the iScript cDNA Synthesis Kit (Bio-Rad, Hercules, CA) as previously described 97 .…”

Section: Chromatin Immunoprecipitation and Chip-pcr Chromatin Immunomentioning

confidence: 99%

Human Chorionic Gonadotropin modulates CXCL10 Expression through Histone Methylation in human decidua

Silasi

You

Simpson

et al. 2020

Sci Rep

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the process of implantation, trophoblast invasion and placentation demand continuous adaptation and modifications between the trophoblast (embryonic) and the decidua (maternal). Within the decidua, the maternal immune system undergoes continued changes, as the pregnancy progress, in terms of the cell population, phenotype and production of immune factors, cytokines and chemokines. Human chorionic gonadotropin (hCG) is one of the earliest hormones produced by the blastocyst and has potent immune modulatory effects, especially in relation to T cells. We hypothesized that trophoblastderived hcG modulates the immune population present at the maternal fetal interface by modifying the cytokine profile produced by the stromal/decidual cells. Using in vitro models from decidual samples we demonstrate that hcG inhibits CXCL10 expression by inducing H3K27me3 histone methylation, which binds to Region 4 of the CXCL10 promoter, thereby suppressing its expression. hCG-induced histone methylation is mediated through EZH2, a functional member of the PRC2 complex. Regulation of CXCL10 expression has a major impact on the capacity of endometrial stromal cells to recruit CD8 cells. We demonstrate the existence of a cross talk between the placenta (hCG) and the decidua (CXCL10) in the control of immune cell recruitment. Alterations in this immune regulatory function, such as during infection, will have detrimental effects on the success of the pregnancy. The coordinated balance between the invading trophoblast and a receptive maternal decidua is critical for the success of pregnancy 1,2. The process of implantation, trophoblast invasion and placentation demand continuous adaptation and modifications between the trophoblast (embryonic) and the decidua (maternal) 3-5. Within the decidua, the maternal immune system undergoes continued modifications, as the pregnancy progresses, in terms of the cell population, phenotype and production of immune factors, cytokines and chemokines 6. These adaptation processes are essential for the normal progression of the pregnancy. The decidua, the pregnant uterine endometrium, has long been considered as a supportive environment for the immune cells and the trophoblast present at the implantation site. However, growing evidence suggest that decidual stromal cells (DSCs) may play a more active role in the regulation of differentiation, migration and function of uterine immune cells 7 as well as in the protection against infections 8. Immune cells are a major cellular component of the human and rodents' pregnant uterus, and their specific role has been an area of active research. During the first trimester of the human pregnancy, 70% of the leukocytes found in the decidua are Natural Killer (NK) cells, 20% to 25% are macrophages, and approximately 1.7% are dendritic cells (DCs) 9-11. In addition, the uterine T cell population expands across gestation, and are mostly regulatory in nature 12. The recruitment of immune cells into the uterus is cell specific and their function is locally controlled 7 .

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Relevance of placental type I interferon beta regulation for pregnancy success

Cited by 29 publications

References 52 publications

Trophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function

Trophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function

Insight Into TLR4-Mediated Immunomodulation in Normal Pregnancy and Related Disorders

Human Chorionic Gonadotropin modulates CXCL10 Expression through Histone Methylation in human decidua

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