Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action

Abstract

A decade ago, we first reported that endometrial biopsy significantly improves the success of pregnancy in IVF patients with recurrent implantation failure, an observation that was later confirmed by others. Recently, we have demonstrated that this treatment elevated the levels of endometrial pro-inflammatory cytokines and increased the abundance of macrophages (Mac) and dendritic cells (DCs). We therefore hypothesised that the biopsy-related successful pregnancy is secondary to an inflammatory response, and aimed at deciphering its mechanism of action. Supporting our hypothesis, we found that the pro-inflammatory TNFa stimulated primary endometrial stromal cells to express cytokines that attracted monocytes and induced their differentiation into DCs. These monocytederived DCs stimulated endometrial epithelial cells to express the adhesive molecule SPP1 (osteopontin (OPN)) and its receptors ITGB3 and CD44, whereas MUC16, which interferes with adhesion, was downregulated. Other implantation-associated genes, such as CHST2, CCL4 (MIP1B) and GROA, were upregulated by monocyte-derived Mac. These findings suggest that uterine receptivity is mediated by the expression of molecules associated with inflammation. Such an inflammatory milieu is not generated in some IVF patients with recurrent implantation failure in the absence of local injury provoked by the biopsy treatment.Reproduction (2015) 149 75-85

Downregulation of genes related to immune and inflammatory response in IVF implantation failure cases under controlled ovarian stimulation

“…Therefore, our findings support the studies which have reported the vital role of stimulation of immune cells to achieve maximum receptivity by endometrium 33. Thus, the adequate activation of pro-inflammatory cascade (stimulation of TH1 response) is requisite for preparation of endometrium during WOI which is then regulated for the activation of TH2-mediated antiinflammatory response to achieve immune tolerance towards invading blastocyst 31,35. Thus, the adequate activation of pro-inflammatory cascade (stimulation of TH1 response) is requisite for preparation of endometrium during WOI which is then regulated for the activation of TH2-mediated antiinflammatory response to achieve immune tolerance towards invading blastocyst 31,35.…”

“…31 However, this hypothesis has not achieved complete success in terms of clinical pregnancies. In IVF failure cases, lack of anti-inflammatory pathway of the maternal immune system has been always highlighted as a cause.…”

Intrauterine infusion of human chorionic gonadotropin before embryo transfer in IVF/ET cycle: The critical review

“…80 Also, endometrial DCs might regulate tissue remodeling and angiogenesis. 81 Taken together, these findings highlight the important role of DCs which is mediated by hCG on the endocrine-immune dialogue within the receptive endometrium at the time of embryo implantation. 81 Taken together, these findings highlight the important role of DCs which is mediated by hCG on the endocrine-immune dialogue within the receptive endometrium at the time of embryo implantation.…”

Congenital Zika syndrome: Pitfalls in the placental barrier

“…Decidual leukocytes, especially dendritic cells (DCs) and natural killer (NK) cells, aid in the apposition, adhesion, and invasion of the blastocyst. 17,18 As the blastocyst invades the decidua, trophoblastic cells augment the population of decidual leukocytes via the secretion of cytokines such as CXCL12, CXCL8, TGFβ, and CCL2, and induce the differentiation of NK cells, macrophages, and CD4+ cells through the secretion of IL-15, GM-CSF, and TGFβ, respectively 19,20 ( Figure 1A). Against this pro-inflammatory background, maternal tolerance to fetal tissue is established, in part through the unique behavior of decidual DCs, which do not migrate to maternal lymphatic vessels upon exposure to fetal antigen, contrary to classical antigen presentation by normal DCs.…”

“…It is now understood that a pro‐inflammatory environment is necessary prior to (not the result of) successful implantation. Decidual leukocytes, especially dendritic cells (DCs) and natural killer (NK) cells, aid in the apposition, adhesion, and invasion of the blastocyst . As the blastocyst invades the decidua, trophoblastic cells augment the population of decidual leukocytes via the secretion of cytokines such as CXCL12, CXCL8, TGFβ, and CCL2, and induce the differentiation of NK cells, macrophages, and CD4+ cells through the secretion of IL‐15, GM‐CSF, and TGFβ, respectively (Figure A).…”