In situ Synthesized Monosodium Urate Crystal Enhances Endometrium Decidualization via Sterile Inflammation During Pregnancy

Abstract

High level of uric acid (UA) is the major origin of gout, and is highly associated with various pregnant complications, such as preeclampsia and gestational diabetes. However, UA’s level and role in the very early stage of pregnancy has not been uncovered. This study aims to investigate the relevance of serum UA and decidualization, an essential process for the establishment and maintenance of pregnancy in women and mice during the early stage of pregnancy. In this study, we first proved that expression level of UA synthase xanthine dehydrogenase (XDH) is highly increased along with decidualization of endometrial stromal cells in both in vitro and in vivo models. Furthermore, serum and endometrial levels of UA are higher in mice with decidualized uterin horn and in vitro decidualized stromal cells. The existence of monosodium urate (MSU) crystal was also confirmed by immunostaining. Next, the roles of MSU on decidualization were explored by both in vitro and in vivo models. Our data shows MSU crystal but not UA enhances the decidualization response of endometrial stromal cells, via the upregulation of inflammatory genes such Ptgs2 and Il11. inhibiting of Cox-2 activity abolishes MSU crystal induced higher expression of decidualization marker Prl8a2. At last, in women, we observed enriched expression of XDH in decidua compare to non-decidualized endometrium, the serum level of UA is significantly increased in women in very early stage of pregnancy, and drop down after elective abortion. In summary, we observed an increased serum UA level in the early stage of women’s pregnancy, and proved that the increased level of UA results from the expressed XDH in decidualizing endometrium of both human and mouse, leading to the formation of MSU crystal. MSU crystal can enhance the decidualization response via inflammatory pathways. Our study has uncovered the association between UA, MSU, and decidualization during the early stage of pregnancy.

Fibroblast activation during decidualization: Embryo-derived TNFα induction of PGI2-PPARδ-ACTIVIN A pathway through luminal epithelium

“…Activated fibroblasts play key roles in the injury response, tumorigenesis, fibrosis, and inflammation through secreting different factors in different physiological or pathological processes [61]. Myofibroblast marker α-SMA has been shown to be one of the important markers of early decidualization in primates[20], and sterile inflammatory secretion of products such as ATP and uric acid after injury has been shown to stimulate fibroblast activation [28; 29] and uterine decidualization [26; 27], so we speculate that fibroblast activation is strongly correlated with decidualization. Because TNC, SPARC, FSP1 and ACTIVIN A were all identified during fibroblast activation, we examined the role of each of these markers during mouse decidualization.…”

“…During the inflammatory phase, the release of these DAMP molecules is able to stimulate the conversion of fibroblasts to αSMA-expressing myofibroblasts [25]. We recently demonstrated that secreted ATP or uric acid under artificial decidualization can induce mouse decidualization [26; 27]. It has been shown that ATP or uric acid can also stimulate fibroblast activation [28; 29].…”

Research on the Mechanism of Asperosaponin VI for Treating Recurrent Spontaneous Abortion by Bioinformatics Analysis and Experimental Validation

“…Further study has shown that the expression of SRC is necessary for invasion and migration of human decidual stromal cells, which exerts vital functions in embryo implantation and human pregnancy [ 47 ]. Prostaglandin G/H synthase 2 (PTGS2) is related to the regulation of inflammatory response, the regulation of which influences the decidualization response of endometrial stromal cells [ 48 ]. Numerous studies have shown that PTGS2 is identified as important regulators of early pregnancy events and plays a vital role in human decidualization and vascularization of the endometrial stroma [ 49 , 50 ].…”

The regulation and function of acetylated high-mobility group box 1 during implantation and decidualization

“…ATP, uric acid, HMGB1 and cell-free fetal DNA are recently identified members of DAMP family ( 12 ). Both ATP and uric acid have been shown to play a role during decidualization ( 13 , 14 ). Both Hmgb1 mRNA and proteins are highly detected in mouse preimplantation uterus ( 15 , 16 ).…”