Immune determinants of endometrial receptivity: a biological perspective

Robertson, Sarah A.; Moldenhauer, Lachlan M.; Green, Ella S.; Care, Alison S.; Hull, M. Louise

doi:10.1016/j.fertnstert.2022.04.023

Cited by 47 publications

(27 citation statements)

References 193 publications

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“…Endometrial immune cells exert immunomodulatory functions that depend on their relative abundance and phenotypes, and they can be altered in response to external and internal environmental signals (i.e., nutrition, metabolism, infection, inflammation, microbial dysbiosis, stress, and developmental programming) [ 4 ]. The infiltration of 28 immune cells in the RIF endometrium was characterized herein using ssGSEA.…”

Section: Discussionmentioning

confidence: 99%

“…However, recurrent implantation failure (RIF) still affects 10–15% of couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment, and the causes underlying up to 50% of these cases remain elusive [ 1 , 2 , 3 ]. The complex implantation process is divided into three distinct phases: apposition, attachment, and invasion [ 3 , 4 , 5 , 6 ]. Apposition occurs when blastocyst L-selectins interact with corresponding ligands from the receptive endometrium.…”

Section: Introductionmentioning

confidence: 99%

“…Although the pathogenesis of unexplained RIF remains controversial, immune cells and immune-related pathways are increasingly recognized for their importance in establishing receptivity and initiating pregnancy. During embryo implantation, immune cells play tissue remodeling and immunomodulatory roles, including promoting epithelial attachment, modulating trophoblast invasion, regulating decidual transformation, remodeling uterine vasculature, and controlling inflammatory activation, along with suppressing inappropriate immunity to paternal human leukocyte antigen (HLA) [ 4 , 7 , 8 ]. Women with RIF may experience changes in the number or function of endometrial immune cells.…”

Section: Introductionmentioning

confidence: 99%

“…Uterine immune cells and molecules are essential elements of endometrial biology. Their complex interactive networks during implantation, fluctuations in abundance and phenotypes within individuals from one cycle to another, and high variability between individuals suggest that they are gatekeepers of the receptive endometrium [ 4 ]. Nevertheless, the molecular mechanisms underlying the pathogenesis of unexplained RIF remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Potential Biomarkers and Endometrial Immune Microenvironment in Recurrent Implantation Failure

Gao

et al. 2023

Biomolecules

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The molecular mechanisms underlying unexplained recurrent implantation failure (RIF) remain unclear. This study aimed at identifying potential biomarkers, exploring relevant signaling pathways, and analyzing the contribution of immune cell infiltration in RIF. Microarray expression datasets were extracted from the Gene Expression Omnibus database to perform bioinformatic analyses. The results showed that ten hub genes may predict RIF with high specificity and sensitivity (area under the curve = 1.000). Protein–protein interaction analysis revealed close interactions between the hub genes and the endometrial receptivity array. The real-time quantitative polymerase chain reaction further validated three potential biomarkers (RAB32, TRIB2, and FAM155B). Functional enrichment analyses indicated that immune pathways were significantly downregulated and lipid metabolism pathways were significantly upregulated in RIF compared with the controls. Significant negative correlations were observed between fatty acid biosynthesis and the immune pathways. Immune cell infiltration, including those in CD56dim natural killer, dendritic, Th1, Th2, and regulatory T cells, as well as macrophages, was significantly reduced in RIF compared with the controls used herein. This study may provide a novel perspective on the diagnosis and treatment of RIF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potential Biomarkers and Endometrial Immune Microenvironment in Recurrent Implantation Failure

Gao

et al. 2023

Biomolecules

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“…The underlying mechanisms of RIF are complex and related to various factors, such as the maternal immune system, embryonic and parental genetics, anatomical characteristics, hematological factors, reproductive tract microbiome, and endocrine milieu ( Franasiak et al, 2021 ). Numerous studies have suggested that immune factors, especially the immune microenvironment of the endometrium, play a crucial role in the process of pregnancy ( Larsen et al, 2013 ; Sebastian-Leon et al, 2018 ; Robertson et al, 2022 ). Both flow cytometry and tissue immunostaining studies showed that human decidual leukocytes in the first trimester are predominantly natural killer (NK) cells (∼70%) and macrophages (∼20%) ( Trundley and Moffett, 2004 ; Bulmer et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Identification and validation of immune cells and hub genes alterations in recurrent implantation failure: A GEO data mining study

Wang

et al. 2023

Front. Genet.

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Introduction: Recurrent implantation failure (RIF) is a distressing problem in assisted reproductive technology (ART). Immunity plays a vital role in recurrent implantation failure (RIF) occurrence and development, but its underlying mechanism still needs to be fully elucidated. Through bioinformatics analysis, this study aims to identify the RIF-associated immune cell types and immune-related genes.Methods: The differentially expressed genes (DEGs) were screened based on RIF-associated Gene Expression Omnibus (GEO) datasets. Then, the enrichment analysis and protein-protein interaction (PPI) analysis were conducted with the DEGs. The RIF-associated immune cell types were clarified by combining single sample gene set enrichment analysis (ssGSEA) and CIBERSORT. Differentially expressed immune cell types-related modules were identified by weighted gene co-expression network analysis (WGCNA) and local maximal quasi-clique merger (lmQCM) analysis. The overlapping genes between DEGs and genes contained by modules mentioned above were delineated as candidate hub genes and validated in another two external datasets. Finally, the microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) that interacted with hub genes were predicted, and the competing endogenous RNA (ceRNA) regulatory network was structured.Results: In the present study, we collected 324 DEGs between RIF and the control group, which functions were mainly enriched in immune-related signaling pathways. Regarding differential cell types, the RIF group had a higher proportion of activated memory CD4 T cells and a lower proportion of γδ T cells in the endometrial tissue. Finally, three immune-related hub genes (ALOX5AP, SLC7A7, and PTGS2) were identified and verified to effectively discriminate RIF from control individuals with a specificity rate of 90.8% and a sensitivity rate of 90.8%. In addition, we constructed a key ceRNA network that is expected to mediate molecular mechanisms in RIF.Conclusion: Our study identified the intricate correlation between immune cell types and RIF and provided new immune-related hub genes that offer promising diagnostic and therapeutic targets for RIF.

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Regulation of iron metabolism in HEC‐1A endometrium cells by macrophage‐derived factors and fractalkine

Pandur,

Pap,

Jánosa

et al. 2024

Cell Biology International

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Macrophages in the endometrium promote receptivity and implantation by secreting proinflammatory cytokines and other factors like fractalkine (FKN). Macrophages are closely linked to regulating iron homeostasis and can modulate iron availability in the tissue microenvironment. It has been revealed that the iron metabolism of the mother is crucial in fertility. Iron metabolism is strictly controlled by hepcidin, the principal iron regulatory protein. The inflammatory cytokines can modulate hepcidin synthesis and, therefore, the iron metabolism of the endometrium. It was proven recently that FKN, a unique chemokine, is implicated in maternal–fetal communication and may contribute to endometrial receptivity and implantation. In the present study, we investigated the effect of activated THP‐1 macrophages and FKN on the iron metabolism of the HEC‐1A endometrial cells. We established a noncontact coculture with or without recombinant human FKN supplementation to study the impact of the macrophage‐derived factors and FKN on the regulation of hepcidin synthesis and iron release and storage of endometrial cells. Based on our findings, the conditioned medium of the activated macrophages could modify hepcidin synthesis via the nuclear factor kappa‐light‐chain‐enhancer of activated B cells, the signal transducer and activator of transcription 3, and the transferrin receptor 2/bone morphogenetic protein 6/suppressor of mothers against decapentaplegic 1/5/8 signaling pathways, and FKN could alter this effect on the endometrial cells. It was also revealed that the conditioned macrophage medium and FKN modulated the iron release and storage of HEC‐1A cells. FKN signaling may be involved in the management of iron trafficking of the endometrium by the regulation of hepcidin. It can contribute to the iron supply for fetal development at the early stage of the pregnancy.

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Immune determinants of endometrial receptivity: a biological perspective

Cited by 47 publications

References 193 publications

Potential Biomarkers and Endometrial Immune Microenvironment in Recurrent Implantation Failure

Potential Biomarkers and Endometrial Immune Microenvironment in Recurrent Implantation Failure

Identification and validation of immune cells and hub genes alterations in recurrent implantation failure: A GEO data mining study

Regulation of iron metabolism in HEC‐1A endometrium cells by macrophage‐derived factors and fractalkine

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