Endometrial inflammation and effect on implantation improvement and pregnancy outcome

Abstract

Implantation failure, which is presently the major barrier in human fertility, is attributed, in many cases, to the failure of the uterus to acquire receptivity. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. These molecules partake in the generation of an inflammatory response followed by the recruitment of immune cells. These cells have shown to be involved in the maternal immune tolerance toward the implanted embryo as well as in the maternal-fetus interaction during pregnancy. Most of the accumulated evidence indicates that embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. Yet, recent findings suggest that a Th1 inflammatory response is also necessary for the acquisition of uterine receptivity. This notion was originally suggested by reports from our and other clinical centers worldwide that IVF patients with repeated implantation failure subjected to endometrial biopsy exhibit a substantial improvement in their chances to conceive. These findings, followed by the demonstration of an elevated pro-inflammatory cytokine/chemokine expression, as well as an increased abundance of immune cells, in the endometrium of these patients, raised the idea that acquisition of uterine receptivity is closely associated with an inflammatory response. This review summarizes the molecular and biochemical evidence that confirm this notion and proposes a mechanism by which injury-induced inflammation improves uterine receptivity and the subsequent pregnancy outcome.Reproduction (2012) 144 661-668

Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure

“…In fact, a KEGG pathway analysis indicated that a number of genes related to natural killer cell cytotoxicity are up‐regulated in thin endometria, suggesting the presence of a cytotoxic condition. Aberrant immunological factors play roles in recurrent miscarriage and implantation failure 6, 26, 27. Interestingly, 56.6% of the patients who experienced embryo implantation failures showed local immune overactivation in the endometrium at the mid‐luteal phase 6.…”

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…These cells have potential inflammatory and antigen-presenting cell functions that could be detrimental to the fetus if the cells were over-activated in response to infection. 7,8,13,14,17,22 CD14 is part of a cognate receptor complex, which includes TLR4 and myeloid differentiation factor 2 and is involved in Mw detection of Gram-negative bacteria via binding to the outer-wall component LPS. 56 IFN-c-primed Mws produced higher levels of pro-inflammatory cytokines and chemokines after stimulation with LPS via the upregulation of CD14, TLR4 and myeloid differentiation factor 2 expression.…”

“…7,8 Whereas gestation has long been recognized as an antiinflammatory Th2 condition, recent studies demonstrated that the process of blastocyst implantation requires a pro-inflammatory Th1 environment. 13,14 The transitory maintenance of this Th1 environment appears to be essential for the growth and survival of trophoblast cells, which in turn produce a balance of pro-and anti-inflammatory cytokines that are linked to the control of leukocyte recruitment, to the regulation of inflammatory activity, and to the promotion of Th2 immune responses. 14 Among the numerous cytokines produced at the implantation site, IFN-c and TNF-a are potent inducers of the pro-inflammatory type-1 phenotype in tissue Mws; 15 in the context of the developing embryo, these cytokines have both beneficial and harmful attributes.…”

“…19,20 Moreover, as observed during recurrent spontaneous abortion and intrauterine infection-associated preterm labor in humans, 7,8 aberrant inflammatory behavior in Mws is associated with spontaneous and endotoxin-mediated abortion in rodents. 21 Thus, even if a pro-inflammatory Th1 environment appears to be required for successful blastocyst implantation, 13,14 the regulation of pro-inflammatory Mw activation within the pregnant uterus may be vital to the avoidance of detrimental Mw functions, which could ultimately lead to placental and fetal demise. Embryonic trophoblast cells have been proposed to participate intensively in this process by producing factors that modulate leukocyte function.…”

Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep

“…However, Th1 (pro-inflammatory) molecules such as tumor necrosis factor alpha (TNFA) and IFNgamma (IFNG) are also necessary for uterine receptivity, implantation, and placental development in some species (Ashkar & Croy 2001, Hess et al 2007, Paulesu et al 2010, Warning et al 2011, Granot et al 2012. Moreover, type I IFNs play an indisputable role during early pregnancy in ruminants, as the conceptus signals its presence to the mother by producing high levels of interferon tau (IFNT).…”