Involvement of Tim-3 in Maternal-fetal Tolerance: A Review of Current Understanding.

As the first T cell immunoglobulin mucin (Tim) family member to be identified, Tim-3 is a powerful immune checkpoint that functions in immunoregulation and induction of tolerance. Conventionally, Tim-3 is considered to play a role in adaptive immunity, especially in helper T cell-mediated immune responses. As researches progress, Tim-3 has been detected in a wider range of cell types, modulating cell function through ligand-receptor interactions and other pathways.

Circadian Regulation of Lipid Metabolism during Pregnancy.

A cluster of metabolic changes occur to provide energy for fetal growth and development during pregnancy. There is a burgeoning body of research highlighting the pivotal role of circadian rhythms in the pathogenesis of metabolic disorders and lipid homeostasis in mammals. Perturbations of the circadian system and lipid metabolism during gestation might be responsible for a variety of adverse reproductive outcomes comprising miscarriage, gestational diabetes mellitus, and preeclampsia.

Identification of m6A Modification Regulated by Dysregulated circRNAs in Decidua of Recurrent Pregnancy Loss.

N6-methyladenosine (m6A) modification is a prevalent modification of messenger ribonucleic acid (mRNA) in eukaryote cells and is closely associated with recurrent pregnancy loss (RPL). Circular RNAs (circRNAs) play critical roles in embryo implantation, trophoblast invasion and immune balance, which are important events during pregnancy. However, how m6A modification is regulated by circRNAs and the potential regulatory mechanism of circRNAs on RPL occurrence remain largely unclassified.

Downregulation of CRHBP is associated with trophoblast invasion inhibition in recurrent pregnancy loss.

In Brief: Corticotropin-releasing hormone binding protein (CRHBP) is fundamental to the stress response and plays an important role in parturition during pregnancy. This study shows that abnormal CRHBP expression could be an early warning sign of recurrent pregnancy loss and that CRHBP knockdown could suppress HTR8/SVneo cell invasion by the PKC signaling pathway via interacting with CRH receptor 2.

Abstract: Trophoblast invasion is critical for placentation and pregnancy success.

Energy metabolism and maternal-fetal tolerance working in decidualization.

One pivotal aspect of early pregnancy is decidualization. The decidualization process includes two components: the differentiation of endometrial stromal cells to decidual stromal cells (DSCs), as well as the recruitment and education of decidual immune cells (DICs). At the maternal-fetal interface, stromal cells undergo morphological and phenotypic changes and interact with trophoblasts and DICs to provide an appropriate decidual bed and tolerogenic immune environment to maintain the survival of the semi-allogeneic fetus without causing immunological rejection.

Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss.

Iron is necessary for various critical biological processes, but iron overload is also dangerous since labile iron is redox-active and toxic. We found that low serum iron and decidual local iron deposition existed simultaneously in recurrent pregnancy loss (RPL) patients. Mice fed with a low-iron diet (LID) also showed iron deposition in the decidua and adverse pregnancy outcomes.

Tim-3 Coordinates Macrophage-Trophoblast Crosstalk via Angiogenic Growth Factors to Promote Pregnancy Maintenance.

T-cell immunoglobulin mucin-3 (Tim-3) is an important checkpoint that induces maternal-fetal tolerance in pregnancy. Macrophages (Mφs) play essential roles in maintaining maternal-fetal tolerance, remodeling spiral arteries, and regulating trophoblast biological behaviors. In the present study, the formation of the labyrinth zone showed striking defects in pregnant mice treated with Tim-3 neutralizing antibodies.

Circadian gene Rev-erbα influenced by sleep conduces to pregnancy by promoting endometrial decidualization via IL-6-PR-C/EBPβ axis.

Background: Sleep disturbance can cause adverse pregnancy outcomes by changing circadian gene expression. The potential mechanisms remain unclear. Decidualization is critical for the establishment and maintenance of normal pregnancy, which can be regulated by circadian genes.

The Critical Roles of Circular RNAs in Basic Research and Clinical Application of Female Reproductive-Related Diseases.

Circular RNAs (circRNAs), produced by precursor mRNAs, are a type of covalently closed circular molecule without 5' caps and 3' polyadenylated tails. Recently, advances in high-throughput sequencing, transcriptomics and bioinformatics, have revealed that circRNAs with specific traits in tissue or cells play emerging roles in both physiological and panthological contexts instead of as simple by-products of transcription. However, bringing circRNAs to the forefront of clinical practice is still a long way off.

Increased Level of Tim-3PD-1CD4T Cells With Altered Function Might Be Associated With Lower Extremity Arteriosclerosis Obliterans.

Lower extremity arteriosclerosis obliterans (LEASO) is a vascular disease that may result in adult limb loss worldwide. CD4T cell-mediated immunity plays a significant role in LEASO. The T cell immunoglobulin and mucin domain 3 (Tim-3) and inhibitory receptor programmed cell death-1 (PD-1) are well-known immune checkpoints that play crucial roles in regulating CD4T cell activation or tolerance.

Pharmacological activation of rev-erbα suppresses LPS-induced macrophage M1 polarization and prevents pregnancy loss.

Background: Circadian rhythm is an important player for reproduction. Rev-erbα, a significant clock gene, is involved in regulating cell differentiation, inflammation and metabolism. Macrophage polarization plays crucial roles in immune tolerance at the maternal-fetus interface, which also modulates the initiation and resolution of inflammation.

Melatonin regulates proliferation and apoptosis of endometrial stromal cells via MT1.

Endometrial dysfunction is an important factor for implantation failure. The function of the endometrium is regulated by multiple factors like sex hormones and circadian rhythms. Endometrial stromal cells (ESCs) are a major cellular component in the endometrium, which is essential for proper physiological activities of the endometrium and the establishment of pregnancy.

Involvement of the Tim-3 Pathway in the Pathogenesis of Pre-Eclampsia.

Current methods of early diagnosis and prevention of pre-eclampsia (PE) are limited; the only available definite treatment is the initiation of delivery and complete removal of the placenta. Inappropriate activation of the immune system is thought to play considerable roles in PE. T cell immunoglobulin mucin-3 (Tim-3) has been reported to regulate immune responses and play important roles in maternal-fetal tolerance during early pregnancy.

Tim-3/CTLA-4 pathways regulate decidual immune cells-extravillous trophoblasts interaction by IL-4 and IL-10.

To obtain a successful pregnancy, the establishment of maternal-fetal tolerance and successful placentation are required to be established. Disruption of this immune balance and/or inadequate placental perfusion is believed to be associated with a lot of pregnancy-related complications, such as recurrent spontaneous abortion, pre-eclampsia, and fetal intrauterine growth restriction. Extravillous trophoblasts (EVTs) have the unique ability to instruct decidual immune cells (DICs) to develop a regulatory phenotype for fetal tolerance.

Melatonin-MT1 signal is essential for endometrial decidualization.

Deficient decidualization of endometrial stromal cells (ESCs) can cause adverse pregnancy outcomes including miscarriage, intrauterine growth restriction, and pre-eclampsia. Decidualization is regulated by multiple factors such as hormones and circadian genes. Melatonin, a circadian-controlled hormone, is reported to be important for various reproductive processes, including oocyte maturation and placenta development.

Decreased level of Eomes+dCD8+ T cells with altered function might be associated with miscarriage.

The T-box transcription factor protein eomesodermin (Eomes) is known for both homeostasis and function of effector and memory CD8+T cells. However, much less is known about the functional regulation of Eomes on CD8+ T cells during pregnancy. In the present study, we concluded the higher Eomes expression dCD8+T cells during normal early pregnancy.

Circadian rhythm-associated Rev-erbα modulates polarization of decidual macrophage via the PI3K/Akt signaling pathway.

Problem: Circadian rhythms are involved not only in the repair and regeneration of the immune system, but may also be associated with regulation of inflammation and immune responses. Rev-erbα could constitute a link between immunity and circadian rhythms since it is a transcription factor that regulates circadian rhythms and has functions in multiple physiological and pathological processes. Decidual macrophages (dMφs) play crucial roles in immune balance at the maternal-fetal interface, and abnormal macrophage polarization is related to adverse pregnancy outcomes, such as infertility, recurrent spontaneous abortion, and preterm labor.

Eomesodermin regulate decidual CD4T cell function during human early pregnancy.

Decidual CD4T (dCD4T) cells play pivotal roles in inducing and maintaining maternal-fetal tolerance. Dysfunctional dCD4T cells are associated with miscarriage. In the present study, we demonstrated that the T-box transcription factor protein eomesodermin (Eomes) was involved in the functional regulation of dCD4T cells during early pregnancy.

Norepinephrine exposure restrains endometrial decidualization during early pregnancy.

Previous studies have focused on the role of norepinephrine on arrhythmias, generalized anxiety disorder, and cancer. This study aimed to investigate the effect of norepinephrine on endometrial decidualization. Artificial decidualization and norepinephrine-treated mice were established in vivo.

Functional regulation of decidual macrophages during pregnancy.

A successful pregnancy requires that the maternal immune system recognizes and tolerates the semi-allogeneic fetus without compromising the capability of protecting both mother and fetus from various pathogens. Decidual macrophages present unique phenotypes to play a key role in the establishment of the immunological aspects of maternal-fetal interaction. Dysfunction of decidual macrophages gives rise to pregnancy complications such as preeclampsia, recurrent spontaneous miscarriage, preterm labor and fetal growth restriction.

Th17/Treg-cell balance in the peripheral blood of pregnant females with a history of recurrent spontaneous abortion receiving progesterone or cyclosporine A.

A successful pregnancy requires the maternal immune system to accept a fetus expressing allogeneic paternal antigens and provide competent responses to infections. Accordingly, maternal-fetal immune abnormalities may have an important role in the development of recurrent spontaneous abortion (RSA). Ever since the establishment of the association between immunologic abnormalities and RSA, various types of immune therapy to restore normal immune homeostasis have been increasingly developed.

Galectin-9 regulates HTR8/SVneo function via JNK signaling.

To obtain a successful pregnancy, trophoblasts must provide a physical barrier, suppress maternal reactivity, produce immunosuppressive hormones locally, and enhance the production of blocking factors that are able to bind to several antigenic sites. Inadequate placental perfusion has been closely associated with several pregnancy-associated diseases. Galectin-9 (Gal-9) has a wide variety of regulatory functions in innate and adaptive immunity during infection, tumor growth, and organ transplantation.

Activation of Rev-erbα attenuates lipopolysaccharide-induced inflammatory reactions in human endometrial stroma cells via suppressing TLR4-regulated NF-κB activation.

Perturbation of the circadian rhythm damages the biological characteristics of cells and leads to their dysfunction. Rev-erbα, an important gene in the transcription-translation loop of circadian rhythm, is involved in regulating the balance between pro-inflammation and anti-inflammation. The disruption of this balance in human endometrial stroma cells (hESCs) destroys their biological behavior function in maintaining the menstrual cycle and embryonic implantation.

Altered frequency and function of spleen CTLA-4+Tim-3+ T cells are associated with miscarriage†.

Normal pregnancy is associated with several immune adaptations in both systemic and local maternal-fetal interface to allow the growth of semi-allogeneic conceptus. A failure in maternal immune tolerance to the fetus may result in abnormal pregnancies, such as recurrent spontaneous abortion. The regulation of T-cell homeostasis during pregnancy has important implications for maternal tolerance and immunity.