SEC5 is involved in M2 polarization of macrophages via the STAT6 pathway, and its dysfunction in decidual macrophages is associated with recurrent spontaneous abortion

Decidual macrophages (dM phi s) 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 dM phi s of patients with RSA, and downregulation of SEC5 expression inhibited M2 polarization and STAT6 phosphorylation, whereas SEC5 overexpression in the M phi s promoted M2 polarization and STAT6 phosphorylation in vitro. We subsequently found that SEC5 interacted with STAT6 in THP-1-derived M phi s. The abundance of phosphorylated STAT6 (pSTAT6) protein was obviously increased, with a predominant distribution in the nucleus, after M2 polarization of M phi s, and SEC5 protein was colocalized with pSTAT6. Moreover, a significantly reduced pSTAT6 expression level was observed in the dM phi s of patients with RSA. M2 polarization of M phi s showed a stimulatory effect on the proliferation and invasion of human extravillous trophoblasts (EVTs) in vitro, and downregulation of SEC5 expression in M phi s effectively reversed this effect. In a mouse model of LPS-induced early pregnancy loss, the uterine SEC5 expression level and the number of M2-M phi s 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 M phi s by interacting with STAT6 and that decreased SEC5 expression inhibits the M2 polarization of dM phi s and results in early pregnancy loss by interfering with the physical activities of EVTs and immunotolerance at the maternal-fetal interface.

Automated summary

The study reveals that SEC5 is involved in regulating the M2 polarization of decidual macrophages (dM phi s) by interacting with STAT6. Decreased SEC5 expression inhibits the M2 polarization of dM phi s, interfering with the physical activities of extravillous trophoblasts (EVTs) and immunotolerance at the maternal-fetal interface, leading to early pregnancy loss.