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. We utilized immortalized human first-trimester extravillous trophoblast cells (HTR8/SVneo) for our functional study and examined the effects of Gal-9 on apoptosis, cytokine production and angiogenesis of HTR8/SVneo cells. Gal-9 inhibited the apoptosis and IFN-γ and IL-17A production, promoted IL-4 production, and coordinated the crosstalk between HTR8/SVneo cells and human umbilical vein endothelial cells via its interaction with Tim-3. Blockade of JNK signaling inhibited Gal-9 activities in HTR8/SVneo cells. In addition, we detected a correlation between low levels of Gal-9 and spontaneous abortion. So Gal-9 could inhibit the apoptosis and proinflammatory cytokine expression, and promote the angiogenesis and IL-4 production in HTR8/SVneo cells via Tim-3 in a JNK dependent manner to help the maintenance of normal pregnancy. These findings possibly identify Gal-9 as a key regulator of trophoblast cells and suggest its potential as a biomarker and target for the treatment of recurrent pregnancy loss.
Mengdie Li, Xiandong Peng, Jinfeng Qian, Fengrun Sun, Chunqin Chen, Songcun Wang, Jianping Zhang, and Meirong Du
Lanting Chen, Fengrun Sun, Mengdie Li, Jinfeng Qian, Meirong Du, Dajin Li, and Songcun Wang
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. The number of Eomes+dCD8+T cells decreased in miscarriage. This Eomes+dCD8+T cell subset also expressed less growth-promoting factors, shifted toward pro-inflammatory phenotype in miscarriage. Primary Trophoblasts and HTR8/SVneo cell line could increase Eomes expression of dCD8+T cells from both normal early pregnancy and miscarriage, which might provide a new strategy for therapy to promote maternal–fetal tolerance and prevent pregnancy loss. These findings indicated that Eomes might be promising early warming targets of miscarriage. In addition, this study suggested that the reproductive safety must be a criterion considered in modulating the dose and function of Eomes in CD8+T cells to reverse T cell exhaustion.
Songcun Wang, Fengrun Sun, Mutian Han, Yinghua Liu, Qinyan Zou, Fuxin Wang, Yu Tao, Dajin Li, Meirong Du, Hong Li, and Rui Zhu
There is delicate crosstalk between fetus-derived trophoblasts (Tros) and maternal cells during normal pregnancy. Dysfunctions in interaction are highly linked to some pregnancy complications, such as recurrent spontaneous abortion (RSA), pre-eclampsia and fetal growth restriction. Hyaluronan (HA), the most abundant component of extracellular matrix, has been reported to act as both a pro- and an anti-inflammatory molecule. Previously, we reported that HA promotes the invasion and proliferation of Tros by activating PI3K/Akt and MAPK/ERK1/2 signaling pathways. While lower HA secretion by Tros was observed during miscarriages than that during normal pregnancies, in the present study, we further confirmed that higher secretion of HA by Tros could induce M2 polarization of macrophages at the maternal–fetal interface by interacting with CD44 and activating the downstream PI3K/Akt-STAT-3/STAT-6 signaling pathways. Furthermore, HA could restore the production of IL-10 and other normal pregnancy markers by decidual macrophages (dMφs) from RSA. These findings underline the important roles of HA in regulating the function of dMφs and maintaining a normal pregnancy.