PD-L1 enhances migration and invasion of trophoblasts by upregulating ARHGDIB via transcription factor PU.1

Abstract

As the main constituent cells of the human placenta, trophoblasts proliferate, differentiate, and invade the uterine endometrium via a series of processes, which are regulated exquisitely through intercellular signaling mediated by hormones, cytokines, and growth factors. Programmed cell death ligand 1 (PD-L1) is a biomarker of the response to immune checkpoint inhibitors and can regulate maternal-fetal immune tolerance during pregnancy progression. Recently, it was found that PD-L1 may regulate obstetric complications by affecting the function of trophoblasts. Therefore, we examined the expression and localization of PD-L1 in the human placenta and observed the effects of PD-L1 on trophoblasts migration and invasion in both the trophoblasts line HTR-8/SVneo and an extravillous explant culture model. Finally, we explored the molecular mechanisms underlying PD-L1-regulated trophoblasts migration and invasion through RNA sequencing and bioinformatics analysis. Our data showed that PD-L1 was mainly expressed in syncytiotrophoblasts and that its protein levels increased with gestational age. Interestingly, the protein expression of PD-L1 was significantly decreased in placentas from pregnancies with preeclampsia compared with normal placentas. Importantly, the migration and invasion abilities of trophoblasts were significantly changed after knockdown or overexpression of PD-L1 in HTR-8/SVneo cells and an extravillous explant culture model, which was partially mediated through the transcription factor PU.1 (encoded by Spi1)-regulated Rho GDP-dissociation inhibitor beta (ARHGDIB) expression. These results suggested that PD-L1 was highly involved in the regulation of trophoblasts migration and invasion, providing a potential target for the diagnosis and treatment of placenta-derived pregnancy disorders.

Reduced NCK1 participates in unexplained recurrent miscarriage by regulating trophoblast functions and macrophage proliferation at maternal-fetal interface

“…HTR-8/SVneo is a cell line commonly used to explore trophoblast function ( Zhang R et al, 2022 ; Zhang D et al , 2023 ), and in this study we found that HTR-8/SVneo expressed NCK1 via Western blotting. Thus, to further explore the possible mechanism of NCK1 in uRM, we selected the trophoblast cell line HTR-8/SVneo.…”

Gestational diabetes mellitus dysregulates the PD-1/PD-L1 axis at the feto-maternal interface

“…extravillous trophoblasts EVTs) show high expression of PD-L1 but with no difference between healthy and GDM samples. High expression of PD-L1 on EVTs has been previously reported 26 . Contrastly, there was a significant decrease in expression of PD-L1 on CD45+ DB leukocytes from individuals with GDM (Figure 3b).…”

Spatial proteomics and transcriptomics of placenta accreta spectrum

“…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).…”

“…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).…”