Decidual macrophages (dMϕs) play critical roles in the establishment of microhomeostasis at the maternal-fetal interface during pregnancy. Impaired macrophage polarization during early pregnancy is associated with recurrent spontaneous abortion (RSA). In the present study, the SEC5 expression level was found to be significantly decreased in primary dMϕs of patients with RSA, and downregulation of SEC5 expression inhibited M2 polarization and STAT6 phosphorylation, whereas SEC5 overexpression in the Mϕs promoted M2 polarization and STAT6 phosphorylation in vitro. We subsequently found that SEC5 interacted with STAT6 in THP-1-derived Mϕs. The abundance of phosphorylated STAT6 (pSTAT6) protein was obviously increased, with a predominant distribution in the nucleus, after M2 polarization of Mϕs, and SEC5 protein was colocalized with pSTAT6. Moreover, a significantly reduced pSTAT6 expression level was observed in the dMϕs of patients with RSA. M2 polarization of Mϕs showed a stimulatory effect on the proliferation and invasion of human extravillous trophoblasts (EVTs) in vitro, and downregulation of SEC5 expression in Mϕs effectively reversed this effect. In a mouse model of LPS-induced early pregnancy loss, the uterine SEC5 expression level and the number of M2-Mϕs at the maternal-fetal interface were significantly reduced. More interestingly, heterozygous SEC5-deficient (SEC5^−/+) pregnant mice were more sensitive to LPS-induced pregnancy loss. Taken together, these data indicate that SEC5 participates in the regulation of M2 polarization of Mϕs by interacting with STAT6 and that decreased SEC5 expression inhibits the M2 polarization of dMϕs and results in early pregnancy loss by interfering with the physical activities of EVTs and immunotolerance at the maternal-fetal interface.

It has been well acknowledged that maternal exposure to fine particulate matters (PM2.5) might lead to poor pregnancy outcomes including the intrauterine growth restriction (IUGR) by interfering with the placental development. Our previous studies have demonstrated that maternal PM2.5 exposure induces IUGR, accompanied with increased maternal circulating TNF alpha level and impaired extravillous trophoblast cells (EVTs) invasion in mice. In this study, HTR8/SVneo cells, the immortalized human EVTs line, were used to assess effects and the underlying molecular mechanisms of nicotinamide on the impaired EVTs invasion. Our results showed that, the placental FLT1 protein level was significantly increased whereas maternal serum nicotinamide concentration was remarkably decreased in PM2.5-exposured pregnant mice at GD17.5 (vaginal plug day=GD0.5), compared to that in normal GD17.5 pregnant mice. FLT1 expression in HTR8/SVneo cells was significantly up-regulated by TNF alpha treatment, and the down-regulated FLT1 expression effectively abated the inhibitory effects of TNF alpha on HTR8/ SVneo cells migration and invasion. Meanwhile, TNF alpha promoted reactive oxygen species (ROS) production and NF-kappa B signaling pathway activation in HTR8/SVneo cells in a dose-dependent manner. Nicotinamide treatment significantly reversed the effects of TNF alpha on cell migration and invasion, as well as the FLT1 expression, ROS production and NF-kappa B pathway activation. In summary, increased TNF alpha induced by PM2.5 exposure inhibits EVTs invasion by activating the ROS/NF-kappa B/FLT1 signaling pathway, and this adverse effect could be attenuated by nicotinamide treatment, suggesting a potential application in the clinical intervention of PM2.5-induced IUGR.