Endometriosis (EMS) is a chronic inflammatory disease characterized by the presence of extrauterine endometrial tissues. It has been previously reported that the refluxed blood containing viable endometrial tissues and the defective elimination of peritoneal macrophages in the pelvic cavity may involve in EMS pathogenesis. However, the mechanism by which macrophages exhibit attenuated phagocytic capability in EMS remains undetermined. Herein, we found that heme, the byproduct of lysed erythrocytes, accumulated abnormally in the peritoneal fluid (PF) of patients with EMS (14.22 μmol/L, 95% confidence interval (CI): 12.54–16.71), compared with the EMS-free group (9.517 μmol/L, 95% CI: 8.891–10.1053). This abnormal accumulation was not associated with the color of PF, phase of the menstrual cycle or severity of the disease. The reduced phagocytic ability of peritoneal macrophages (pMφs) was observed in the EMS group. Consistently, a high-concentration (30 μmol/L) heme treatment impaired EMS-pMφs phagocytosis more than a low-concentration (10 μmol/L) heme treatment. A similar phenomenon was observed in the EMS-free control pMφs (Ctrl-pMφs) and the CD14+ peripheral monocytes (CD14+ Mos). These results indicated that a high heme concentration exhibits a negative effect on macrophage phagocytosis, which supplements the mechanism of impaired scavenger function of pMφs in EMS.

During the implantation of embryo, apoptosis is inevitable. These apoptotic cells (AC) are removed by efferocytosis, which lls the macrophage with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to the interrelationship between efferocytosis metabolism and the immune behavior of decidual macrophages (dMΦs) and its effect on pregnancy outcome. Here we report a positive feedback of IL-33/ST2-AXL-efferocytosis leading to pregnancy failure through metabolic reprogramming of dMΦs. We compared the serum level of IL-33, sST2, along with IL-33, ST2, efferocytosis and metabolism of dMΦs from both normal gravidas and unexplained recurrent pregnancy loss (RPL) patients. And we revealed the disturbance of IL-33/ST2 axis, increased apoptotic cells and elevated efferocytosis of dMΦs from the patients with RPL. Afterwards the dMΦs swallowing so many apoptotic cells secreted more sST2 and less TGF-β, which polarized dMΦs towards M1 phenotype.Moreover, the elevated sST2 biased the efferocytosis metabolism of RPL dMΦs towards oxidative phosphorylation and exacerbated the disruption of IL-33/ST2 signaling pathway. The metabolic disorders also led to the dysfunction of efferocytosis, resulting in more uncleared apoptotic cells and the secondary necrosis occurred. We also screened efferocytotic molecule AXL regulated by IL-33/ST2. This positive feedback of IL-33/ST2-AXL-efferocytosis led to pregnancy failure. And the IL-33 knockout mice demonstrated poor pregnancy outcomes, and exogenous supplementation of mouse IL-33 could partially alleviate the fate of embryo losses. These ndings highlight a new etiological mechanism whereby dMΦs leverage immunometabolism for the homeostasis of microenvironment at the maternal-fetal interface.

This study indicates that IL-33 secreted by dMφs promotes M2 bias at the feto-maternal interface, and as a result, RSA might attribute to the disturbance of IL-33/ST2 axis and the enhancement of efferocytosis of dMφs subsequently.

It is well established that embryonic chromosomal abnormalities (both in the number of chromosomes and the structure) account for 50% of early pregnancy losses. However, little is known regarding the potential differences in the incidence and distribution of chromosomal abnormalities between patients with sporadic abortion (SA) and recurrent pregnancy loss (RPL), let alone the role of submicroscopic copy-number variations (CNVs) in these cases. The aim of the present study was to systematically evaluate the role of embryonic chromosomal abnormalities and CNVs in the etiology of RPL compared with SA. Over a 3-year period, 1556 fresh products of conception (POCs) from miscarriage specimens were investigated using single nucleotide polymorphism array (SNP-array) and CNV sequencing (CNV-seq) in this study, along with further functional enrichment analysis. Chromosomal abnormalities were identified in 57.52% (895/1556) of all cases. Comparisons of the incidence and distributions of chromosomal abnormalities within the SA group and RPL group and within the different age groups were performed. Moreover, 346 CNVs in 173 cases were identified, including 272 duplications, 2 deletions and 72 duplications along with deletions. Duplications in 16q24.3 and 16p13.3 were significantly more frequent in RPL cases, and thereby considered to be associated with RPL. There were 213 genes and 131 signaling pathways identified as potential RPL candidate genes and signaling pathways, respectively, which were centered primarily on six functional categories. The results of the present study may improve our understanding of the etiologies of RPL and assist in the establishment of a population-based diagnostic panel of genetic markers for screening RPL amongst Chinese women.

No abstract