Knocking down macrophages Caspase-6 through HMGB1 coordinates macrophage trophoblast crosstalk to suppress ferroptosis and alleviate preeclampsia.

OBJECTIVE: Caspase-6 is an important regulatory factor in innate immunity, inflammasome activation, and host defense, but its role in preeclampsia (PE) is unknown. This study aims to investigate the mechanism of Caspase-6 in the interaction between PE rats and macrophage-trophoblast cells, in order to provide a new theoretical basis for the treatment of PE. METHODS: Co-cultures of THP-1 cells and HTR8/SVneo cells were employed to investigate the HMGB1 signaling in macrophages (transfection with si-Caspase-6) and HTR8/SVneo cells. The PE rat model was constructed by using the reduced uterine perfusion pressure (RUPP) surgery to explore the therapeutic effects of bone marrow-derived macrophages (BMDM) transfected with si-Caspase-6 in PE rats. ELISA, Western blot, immunofluorescence, etc., were employed to characterize the expression of ferroptosis-related markers. RESULTS: Caspase-6 expression was significantly increased in CD14+ macrophages in the placental tissue of PE rats. Overexpression of Caspase-6 in THP-1 cells induced ferroptosis of HTR8/SVneo cells, but this process was blocked by anti-HMGB1 neutralizing antibody. Knockdown of Caspase-6 in macrophages could alleviate ferroptosis of HTR8/SVneo cells and restore its basic characteristics. Knockdown of Caspase-6 in BMDM downregulated ferroptosis in placental tissue of PE rats through HMGB1, thereby improving the disease phenotype in rats. CONCLUSION: Knocking down Caspase-6 in BMDM regulated the crosstalk between macrophages and HTR8/SVneo cells through HMGB1, inhibiting HTR8/SVneo cell ferroptosis, thereby improving adverse pregnancy outcomes of PE.

Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data.

This study investigated the implication of monitoring hypertensive disorders in pregnancy (HDP) to prevent preeclampsia (PE) in pregnant women of advanced maternal age. Between January 2016 and April 2021, 262 consecutive pregnant women aged ≥40 years were recruited. Extensive monitoring of hypertensive disorders in pregnancy, including blood hypercoagulability screening and subsequent interventions, was performed in 129 pregnant women in our university hospital. The remaining 133 patients from other centres, who did not receive antenatal maternal pregnancy screening and preventive intervention during the same period, constituted the non-intervention group enabling comparison to mimic a trial. The incidences of hypertensive disorders, mild and severe PE, eclampsia, and chronic hypertension complicated by PE in the intervention group were significantly lower than in the non-intervention group (10.08 versus 20.30%, 8.52 versus 18.80%, 7.75 versus 21.05%, 0 versus 3.01%, and 3.86 versus 15.04%, respectively; P < 0.05). Premature birth, low birth weight, and foetal loss were significantly rarer in the intervention group than in the non-intervention group (6.98 versus 24.81%, 7.75 versus 21.80%, and 0.78 versus 14.29% respectively; P < 0.001). The comparison of MP with routine blood coagulation biochemical examination found that the MP detection system of Beijing Yes Medical Devices Co., Ltd., had similar sensitivity as thromboelastogram. Still, it was significantly better than the routine biochemical indicators (P < 0.01). Based on MP parameters, early anticoagulant treatment with low-molecular-weight heparin or low-dose aspirin in pregnant women with hypercoagulability can effectively prevent the occurrence of PE and significantly improve the prognosis of both mothers and infants.

Long non-coding RNA lnc-DC in dendritic cells regulates trophoblast invasion via p-STAT3-mediated TIMP/MMP expression.

PROBLEM: Dendritic cells are the primary antigen-presenting cells that contact trophoblasts at the beginning of pregnancy. Excessive DCs maturity is described in some pregnancy complications, such as pre-eclampsia and fetal growth restriction, which are characterized by impaired trophoblast invasion. However, the mechanism is unclear. The long non-coding RNA long non-coding RNA DC (lnc-DC) is expressed exclusively in conventional human DCs and induces DC differentiation and maturation by promoting signal transducer and activator of transcription 3 (STAT3) phosphorylation. Our previous investigation proved lnc-DC and p-STAT3 are elevated in pre-eclampsia. This research is to study the mechanism of lnc-DC and trophoblast invasion. METHOD OF STUDY: We transfected DCs with lnc-DC shRNA or a lentivirus for lnc-DC overexpression and cocultured these treated DCs with trophoblast under different conditions. Transwell assay and wound healing assay were used to detect the trophoblast invasion ability. We also tested the matured DCs and Th1 cells as well as the p-STAT3. RESULTS: We found that lnc-DC promoted DC maturation and inhibited trophoblast invasion without the involvement of CD4+ T cells. And the p-STAT3 agonist could reverse the lnc-DC function. CONCLUSION: Mature DCs may be involved in altering trophoblast invasion through the overexpression of lnc-DC, which increases p-STAT3 levels and the tissue inhibitor of metalloproteinase-1 (TIMP-1)/matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-2 (TIMP-2)/matrix metalloproteinase-2 (MMP-2) ratios. Thus, lnc-DC is a promising novel target for regulating trophoblast invasion.