Embryo Quality Conditions the Secretory Profile of Tolerogenic Dendritic Cell DC-10 During the Peri-Implantation Period.

PROBLEM: The decidualization process conditions monocytes to the immunosuppressive and tolerogenic dendritic cell (DC)-10 profile, a DC subset with high IL-10 production. Since the implantation process implies an embryo-endometrium-immune crosstalk, here we focused on the ability of embryonic soluble factors to modify decidual DC conditioning accordingly with its quality. METHOD OF STUDY: Human endometrial stromal cell line (HESC) decidualized with medroxyprogesterone and dibutyryl-cAMP (Dec) was stimulated with human embryo-conditioned media (ECM), classified as normal (ND) or impaired developed (ID) for 48 h (n = 18/group). Monocytes isolated from six healthy women were differentiated to DCs with rhGM-CSF+rhIL-4 in the presence/absence of conditioned media (CM) from decidualized cells stimulated with ECM or nontreated. RESULTS: We found that decidualized cells stimulated with ECM sustain a myeloid regulatory cell profile on monocyte-derived culture with increased frequency of CD1a-CD14+ and CD83+CD86low cells. ND-Dec sustained the higher expression of the DC-10 markers, HLA-G and IL-10 whereas ID-Dec diminished IL-10 production (ID-Dec: 135 ± 37.4 vs. Dec: 223.3 ± 49.9 pg/mL, p < 0.05). The treatment with ECM-Dec sustained a higher IL-10 production and prevented the increase of CD83/CD86 after LPS challenge regardless of embryo quality. Notably, TNF-α production increased in ID-Dec cultures (ID-Dec: 475.1 ± 134.7 vs. Dec: 347.5 ± 98 pg/mL, p < 0.05). CONCLUSIONS: Although remaining in a tolerogenic profile compatible with DC-10, DCs can differentially respond to decidual secreted factors based on embryo quality, changing their secretome. These results suggest that in the presence of arrested embryo, DCs could differentially shape the immunological microenvironment, contributing to arrested embryo clearance during the menstrual phase.

Management of patients with endometriosis and infertility: laparoscopic treatment and spontaneous pregnancy rate.

OBJECTIVE: To evaluate factors involved in spontaneous pregnancy rate after surgery for endometriosis in patients with endometriosis and infertility. METHODS: This retrospective study spanned from 2014 to 2020 and included a follow-up period of two years of patients with endometriosis-related infertility who underwent laparoscopic surgery. Women aged 25 to 43 years with patent tubes, no/mild male factor and no other infertility factors were selected and grouped according to fertility management as follows: patients immediately prescribed ART (16.5%, ART-p); patients who chose not to undergo ART (83.5%) and achieved spontaneous pregnancy (71.8% SP-p); and patients who first chose not to undergo ART but had it subsequently (28.2%, NSP-p). RESULTS: A total of 200 patients were analyzed. Of the 167 patients who waited for spontaneous pregnancy, 71.8% achieved it. We observed a tendency of higher endometriosis ASRM scores in the ART-p group compared with patients who waited for spontaneous pregnancy, and lower scores in individuals that achieved spontaneous pregnancy. When we looked at how long it took to achieve pregnancy, we found that individuals in the SP-p group achieved pregnancy in 5.7 months, while subjects in the NSP-p group took 1.8 times longer than their peers in the SP-p group (p<0.001). However, once prescribed ART, the individuals in the NSP-p group achieved pregnancy within a similar time when compared with subjects in the SP-p group. In order to identify individuals that might benefit from ART early on, we performed a multivariable analysis and developed a decision tree (81.3% accuracy and 53.3% sensitivity). CONCLUSIONS: The present results indicated that, after surgery, the majority of patients achieved spontaneous pregnancy. The decision tree proposed in this study allows the early identification of patients who might require ART, thus decreasing the time between surgery and pregnancy and improving overall outcomes.

Monocyte immunometabolic reprogramming in human pregnancy: contribution of trophoblast cells.

Immunometabolism research is uncovering the relationship between metabolic features and immune cell functions in physiological and pathological conditions. Normal pregnancy entails a fine immune and metabolic regulation of the maternal-fetal interaction to assist the energetic demands of the fetus with immune homeostasis maintenance. Here, we determined the immunometabolic status of monocytes of pregnant women compared with nonpregnant controls and its impact on monocyte anti-inflammatory functions such as efferocytosis. Monocytes from pregnant women (16-20 wk) and nonpregnant age-matched controls were studied. Single cell-based metabolic assays using freshly isolated monocytes from both groups were carried out in parallel with functional assays ex vivo to evaluate monocyte efferocytic capacity. On the other hand, various in vitro metabolic assays with human monocytes or monocyte-derived macrophages were designed to explore the effect of trophoblast cells in the profiles observed. We found that pregnancy alters monocyte metabolism and function. An increased glucose dependency and enhanced efferocytosis were detected in monocytes from pregnant women at resting states, compared with nonpregnant controls. Furthermore, monocytes display a reduced glycolytic response when stimulated with lipopolysaccharide (LPS). The metabolic profiling of monocytes at this stage of pregnancy was comparable with the immunometabolic phenotypes of human monocytes treated in vitro with human first trimester trophoblast cell conditioned media. These findings suggest that immunometabolic mechanisms are involved in the functional shaping of monocytes during pregnancy with a contribution of trophoblast cells. Results provide new clues for future hypotheses regarding pregnancies complicated by metabolic disorders.NEW & NOTEWORTHY Immunometabolism stands as a novel perspective to understand the complex regulation of the immune response and to provide small molecule-based therapies. By applying this approach to study monocytes during pregnancy, we found that these cells have a unique activation pattern. They rely more on glycolysis and show increased efferocytosis/IL-10 production, but they do not have the typical proinflammatory responses. We also present evidence that trophoblast cells can shape monocytes into this distinct immunometabolic profile.