Journal
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2022.891748
Keywords
SEC5; STAT6; macrophage polarization; maternal-fetal interface; recurrent spontaneous abortion
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Funding
- National Natural Science Foundation of China [31801248, 82001640, 81873834]
- Natural Science Foundation of Shanghai [20ZR1447900]
- Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation [CX 2022-07]
- Youth Science Fund Project from The Second Hospital of Tianjin Medical University [2019ydey15]
- Tianjin Health Science and Technology Project [KJ20104]
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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.
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.
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