The programmed cell death protein 1 (PD1) and the programmed cell death ligand 1 (PD-L1) are significantly downregulated on macrophages and Hofbauer cells in the placenta of preeclampsia patients

Mittelberger, Johanna; Seefried, Marina; Löb, Sanja; Kühn, Christina; Franitza, M; Garrido, F; Wild, Carl Mathis; Ditsch, Nina; Jeschke, Udo; Dannecker, Christian

doi:10.1016/j.jri.2023.103949

Cited by 11 publications

(4 citation statements)

References 40 publications

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“…PD-1 and its ligand PD-L1 are expressed in syncytiotrophoblast, cytotrophoblasts and EVT (79). Here, they promote an immunosuppressive environment at the maternal-fetal interface (79–81). Among their role in modulating maternal immune cells, PD-1 and PD-L1 expression by trophoblast cells results in macrophage polarization to an M2 phenotype, the dominant macrophage population in the decidua, resulting in increased CD14 macrophages (82).…”

Section: Resultsmentioning

confidence: 99%

Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

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In severe Placenta Accreta Spectrum (PAS), trophoblasts gain deep access in the myometrium (placenta increta). This study investigated alterations at the fetal-maternal interface in PAS cases using a systems biology approach consisting of immunohistochemistry, spatial transcriptomics and proteomics. We identified spatial variation in the distribution of CD4+, CD3+and CD8+T-cells at the maternal-interface in placenta increta cases. Spatial transcriptomics identified transcription factors involved in promotion of trophoblast invasion such as AP-1 subunits ATF-3 and JUN, and NFKB were upregulated in regions with deep myometrial invasion. Pathway analysis of differentially expressed genes demonstrated that degradation of extracellular matrix (ECM) and class 1 MHC protein were increased in increta regions, suggesting local tissue injury and immune suppression. Spatial proteomics demonstrated that increta regions were characterised by excessive trophoblastic proliferation in an immunosuppressive environment. Expression of inhibitors of apoptosis such as BCL-2 and fibronectin were increased, while CTLA-4 was decreased and increased expression of PD-L1, PD-L2 and CD14 macrophages. Additionally, CD44, which is a ligand of fibronectin that promotes trophoblast invasion and cell adhesion was also increased in increta regions. We subsequently examined ligand receptor interactions enriched in increta regions, with interactions with ITGβ1, including with fibronectin and ADAMS, emerging as central in increta. These ITGβ1 ligand interactions are involved in activation of epithelial–mesenchymal transition and remodelling of ECM suggesting a more invasive trophoblast phenotype. In PAS, we suggest this is driven by fibronectin via AP-1 signalling, likely as a secondary response to myometrial scarring. Overall, this study suggests the biological processes leading to deep trophoblast invasion in the myometrium in placenta increta are as a result of upregulation of transcription factors and subsequent genes and proteins which promote trophoblast invasion. This occurs in a locally immune suppressed environment, with increased ECM degradation suggesting these findings are secondary to iatrogenic uterine injury.Significance statementPlacenta Accreta Spectrum (PAS) is a rare pregnancy complication, where the placenta fails to separate from the womb resulting in severe bleeding, which is associated with significant maternal morbidity and mortality. As Caesarean section rates increase, the incidence of PAS is increasing. The underlying pathophysiology of PAS is poorly understood. Here, we apply a spatial multi-omic approach to explore the biologic changes at the maternal-fetal interface in severe PAS (placenta increta). Using spatial transcriptomics and proteomics, we identified genes and proteins that are dysregulated in severe PAS involving processes such as extracellular matrix degradation, local immune suppression and promotion of epithelial–mesenchymal transition. This study provides new insights into the biological changes and underlying pathophysiology leading to placenta increta.

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Section: Resultsmentioning

confidence: 99%

Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

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“…See Supplementary Table 5 for full results. Recently, CD163 expression in Hofbauer cells was associated with BMI, gravidity, and fetal birthweight [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

“…Although MDMX was not measured, we believe it would have been decreased also. Lower MDMX levels (Supplementary Tables 5 , 9 ) could reflect the decreased numbers of HC in preeclampsia [ 43 , 44 ]. What can cause the decrease of HC?…”

Section: Discussionmentioning

confidence: 99%

“…An association of gravidity with MDMX was found by univariable and multivariable regression analysis (Supplementary Tables 5 , 9 ). Gravidity was recently associated with HC levels determined by CD163 immunostaining [ 44 ] and HC gene signatures are influences by gravidity [ 79 ]. While multigravida women have shorter telomeres and increased DNA methylation age [ 80 ], a role of p53 and MDMX on telomere length is not established in normal human tissues, to the best of our knowledge.…”

Section: Discussionmentioning

confidence: 99%

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Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor

Ho,

Chaput,

Sinkey

et al. 2024

Cell Commun Signal

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VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20–150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood–brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10–8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.

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Decidual macrophage: a reversible role in immunotolerance between mother and fetus during pregnancy

Jiang,

2024

Arch Gynecol Obstet

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The programmed cell death protein 1 (PD1) and the programmed cell death ligand 1 (PD-L1) are significantly downregulated on macrophages and Hofbauer cells in the placenta of preeclampsia patients

Cited by 11 publications

References 40 publications

Spatial proteomics and transcriptomics of placenta accreta spectrum

Spatial proteomics and transcriptomics of placenta accreta spectrum

Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor

Decidual macrophage: a reversible role in immunotolerance between mother and fetus during pregnancy

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