M2 macrophage‐derived G‐CSF promotes trophoblasts EMT, invasion and migration via activating PI3K/Akt/Erk1/2 pathway to mediate normal pregnancy

Abstract

Trophoblasts are important parts of the placenta and exert vital roles in the maternal‐foetal crosstalk, and sufficient trophoblasts migration and invasion is critical for embryo implantation and normal pregnancy. Macrophages, as the major components of decidual microenvironment at maternal‐foetal interface, can interact with trophoblasts to participate in the regulation of normal pregnancy. Previously, our group have demonstrated that trophoblasts could induce macrophages polarization to M2 subtype by secreting interleukin‐6 (IL‐6); however, the understanding of macrophages regulating the migration and invasion of trophoblasts is limited. In the present study, we used the co‐cultured model to further investigate the effects of macrophages on trophoblasts migration and invasion. Our results showed that co‐culture with macrophages promoted epithelial‐to‐mesenchymal transition (EMT) of trophoblasts, thereby enhancing their migrative and invasive abilities. Further experiments revealed that M2 macrophage‐derived G‐CSF was a key factor, which promoted the EMT, migration and invasion of trophoblasts via activating PI3K/Akt/Erk1/2 signalling pathway. Clinically, G‐CSF was highly expressed in placental villous tissues of normal pregnancy patients compared to patients with recurrent spontaneous abortion, and its expression level was significantly correlation with EMT markers. Taken together, these findings indicate the important role of M2 macrophages in regulating trophoblasts EMT, migration and invasion, contributing to a new insight in concerning the crosstalk between macrophages and trophoblasts in the establishment and maintenance of normal pregnancy.

G-CSF: One of The Vehicles for Communication Between Trophoblasts and Macrophages, Which May Cause Problems in Recurrent Spontaneous Abortion

“…The association between the overexpression of NLRP3 in ammasomes and RSA had been con rmed, which was consistent with our experimental results [6,28]. Therefore, we believe that the loss of G-CSF, on the one hand, disrupts the function of trophoblasts, and on the other hand, interferes with the pro-in ammatory and anti-in ammatory balance at the mother-foetal interface through macrophages, which in turn leads to impaired trophoblasts function [7,29] and ultimately induces RSA.…”

Decreased USP2a Expression Inhibits Trophoblast Invasion and Associates With Recurrent Miscarriage

“…Then they begin to transition to a mixed M1/M2 profile when the trophoblasts establish attachment into the endometrium and invade the uterine stroma. In general, decidual macrophages are characterized by an immunosuppressive phenotype as M2 polarization secreting IL-10, TGF-β, and G-CSF, supporting fetal-maternal immune tolerance during implantation ( 45 , 46 ). Abnormal macrophage polarization is related to many pregnancy complications, such as PE, premature birth, and RM ( 47 ).…”

MNSFβ Regulates TNFα Production by Interacting with RC3H1 in Human Macrophages, and Dysfunction of MNSFβ in Decidual Macrophages Is Associated With Recurrent Pregnancy Loss

“…In addition, although it was found that dMϕ had no effect on the invasion of primary EVTs ( 37 ), it was also reported that LPS-stimulated peripheral blood monocytes could inhibit HTR-8/SVneo cell invasion by the secretion of TNFα ( 38 ), and M2 macrophages showed an enhanced promotion effect on trophoblast cell motility ( 39 ); these suggest that the dMϕ might inhibit EVTs invasion in early pregnancy. However, in this study, we found that the dMϕ from normal women in early pregnancy exerted a stimulatory effect on HTR-8/SVneo cell motility ( Figure 4C ).…”