Year: 2022
Type: article
Abstract: A successful pregnancy depends on numerous processes that include maternal immune tolerance of the fetus and proper function of specialized placental cells, known as trophoblasts, that rapidly expand and differentiate in an oxygen-dependent manner after embryo implantation. Maternal immune tolerance is thought to be coordinated by several suppressive immune cell types that reside within the specialized endometrial lining of the uterus where the placenta implants—the decidua. These immune cells include regulatory T cells, uterine natural killer cells, and anti-inflammatory (M2) macrophages. Cytotrophoblasts (CytTs), which comprise the inner cell layer of the placental villi, fuse together to form the multinucleated syncytiotrophoblast (SynT), a specialized cell that mediates gas, nutrient, and waste exchange between the mother and fetus. Because the SynT comprises the outer cell layer of the placental villi at the maternal–fetal interface, they interact closely with immune cells residing in the decidua and the maternal blood. Thus, the SynT also plays an important role in both local and systemic maternal immune tolerance. To support local immune tolerance, SynTs maintain elevated levels of suppressive proteins when compared with CytTs including the immune checkpoint protein programmed death-ligand 1 (PD-L1) (1). This suggests that trophoblast-mediated immune suppression may require CytT fusion, an idea that needs further exploration. SynTs have also been shown to secrete immunosuppressive proteins, such as PD-L1, within exosomes to mediate systemic immune tolerance (2). While these examples focused on 1 immune checkpoint protein, SynTs express several other immune suppressive factors, including metabolizing enzymes like heme oxygenase-1 (HMOX1) and indoleamine 2,3-dioxygenase; cytokines like growth and differentiation factor-15 (GDF-15); and transcription factors like aryl hydrocarbon receptor (AhR), CCAAT/enhancer-binding protein-beta (C/EBPβ), peroxisome proliferator-activated receptor γ, and nuclear erythroid 2-related factor 2 (NRF2/NFE2L2). However, SynTs lack expression of immune stimulatory proteins such as major histocompatibility-I/II, suggesting that maternal tolerance is maintained in part via a SynT-specific immune suppressive program. Despite the importance of SynTs to maternal tolerance, the molecular mechanisms regulating SynT-mediated immune suppression remain underexplored due to a lack of dependable and physiologically relevant cell culture models of trophoblast differentiation. The Mendelson group overcame this limitation using a novel human trophoblast stem cell (hTSC) model, in addition to primary human CytT isolated from mid-gestation placentas and mouse models (3). Since CytT differentiation into SynT relies on increased oxygen levels, hTSCs were cultured in hypoxic (2% O2) or 20% O2 conditions to stimulate differentiation into SynTs. Only hTSCs cultured under 20% O2 conditions upregulated SynT-specific markers, demonstrating successful modeling of trophoblast differentiation. Transcription factors known to regulate this process were found to be expressed in hTSCs upon SynT differentiation in 20% O2. Moreover, levels of NRF2, a powerful regulator of the antioxidant response, and C/EBPβ, a master regulator of the inflammatory response, were elevated in hTSCs cultured in 20% O2 conditions, but remained low in those cultured under hypoxic conditions, demonstrating the importance of these transcription factors to SynT differentiation. Further analysis in hTSCs and primary trophoblast cultures revealed that NRF2 directly binds and regulates transcription of several immune suppressive factors in SynTs including the heme metabolizing enzyme HMOX1, the kynurenine receptor AhR, the stress responsive cytokine GDF-15, and PD-L1. In NRF2 knockout mice, placentas and fetuses were significantly smaller and placentas manifested reduced expression of each one of these immune suppressive factors. Conversely, NRF2 knockout placentas had enhanced expression of proinflammatory cytokines like interleukin-1β when compared with wild-type controls. Together, these results suggest that NRF2 supports maternal immune tolerance by regulating an immune suppressive program that may act both locally in the uterus and systemically throughout the mother. These findings may also detail a molecular mechanism that explains the link between NRF2 loss in the placenta and pre-eclampsia, a condition that arises when there is insufficient maternal blood flow to the placenta and can be deadly to both the mother and the fetus (4). The authors previously demonstrated that NRF2 regulates SynT differentiation in part through transcriptional induction of the microRNA miR-1246 (5). MicroRNAs have an established role at the maternal–fetal interface and in many other pathologies where immune recognition is dampened, such as in cancer. In fact, trophoblasts and cancer cells utilize many of the same immune suppressive pathways, indicating that cancers may avoid immune recognition of neoantigens by mimicking normal developmental processes utilized by trophoblasts. These parallels between trophoblasts and cancer cells are strengthened by the fact that many of the immune suppressive factors identified by the Mendelson group as NRF2 regulated in trophoblasts were also expressed in aggressive breast cancer cells, where they are directly regulated by members of the microRNA-200 family (6, 7). Loss of miR-200c supports immune suppression and progression in several types of carcinomas, while in trophoblasts its loss is desirable because it limits cell death and supports proper invasion and placental formation (7, 8). Recent evidence suggests that pre-eclampsia is caused by trophoblasts that aberrantly maintain miR-200c expression, and in this situation miR-200c levels and pre-eclampsia may be controlled by treatment with the nonsteroidal anti-inflammatory drug aspirin (7). Yet, whether aspirin or decreased inflammation regulates miR-200c in cancer cells or whether local immune suppression in trophoblasts is mediated by microRNAs requires further exploration. Since trophoblasts also induce systemic changes in immune tolerance through exosome secretion and these exosomes are known to contain microRNAs, it is also possible that systemic delivery of trophoblast microRNAs may enhance immunomodulation or other pregnancy-associated changes outside of the uterus. Although microRNA-based therapies have been met with some clinical challenges, there is wide interest in developing therapeutics to activate and/or inhibit NRF2. While these drugs have mostly been tested in cancer models, further exploration of the parallels between trophoblasts and cancer cells may reveal NRF2 or additional factors as actionable targets to both prevent pre-eclampsia and limit cancer progression. aryl hydrocarbon receptor CCAAT/enhancer-binding protein-beta cytotrophoblast growth and differentiation factor-15 heme oxygenase-1 human trophoblast stem cell nuclear erythroid 2-related factor 2 programmed death-ligand 1 syncytiotrophoblast The authors have no conflicts of interest to disclose. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Source: Endocrinology
Authors: Michelle M Williams, Jennifer K Richer
Institution: University of Colorado Anschutz
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4284889163