Increased levels of HMGB1 in trophoblastic debris may contribute to preeclampsia

Abstract

Preeclampsia is triggered by an as yet unknown toxin from the placenta. Antiphospholipid antibodies (aPL), a strong risk factor for preeclampsia, have been shown to induce the production of toxic trophoblastic debris from the placenta. High mobility group box 1 (HMGB1) is a proinflammatory danger signal, and the expression of it has been reported to be increased in preeclampsia. This study examined whether aPL or preeclamptic sera increase the expression of HMGB1 in the syncytiotrophoblast or trophoblastic debris. Trophoblastic debris from normal placental explants that had been cultured with aPL or preeclamptic sera was exposed to endothelial cells. Endothelial cell activation was quantified by cell-surface ICAM-1 expression and U937 monocyte adhesion. The expression of HMGB1 in placental explants and trophoblastic debris that had been treated with aPL or preeclamptic sera was measured by immunohistochemistry and western blotting. The expression of the receptor for advanced glycation end products (RAGE) in endothelial cells was quantified by western blotting. Compared with controls, the expression of HMGB1 in the cytoplasm of the syncytiotrophoblast and trophoblastic debris was increased by treating placental explants with aPL or preeclamptic sera. The increased levels of HMGB1 contributed to endothelial cell activation, mediated in part by the RAGE. Preeclamptic sera and aPL both induced an increase in the cytoplasmic levels of the danger signal HMGB1 in trophoblastic debris. This increased HMGB1 in trophoblastic debris may be one of the toxic factors released from the placenta in preeclampsia.

Feasibility of placenta-derived mesenchymal stem cells as a tool for studying pregnancy-related disorders

“…Microarray analysis indicated a number of genes that were up- or down-regulated by the miR-518b mimic. Among the 124 target genes down-regulated more than 2-fold (Supplementary Table S1), two genes (tyrosine hydroxylase: TH and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1: HSD3B1 ) were previously demonstrated to be involved in the pathogenesis of preeclampsia202122, and five genes (endothelin receptor type A: EDNRA , advanced glycosylation end product-specific receptor: AGER , wingless-type MMTV integration site family member 2: WNT2 , complement component 9: C9 , and transient receptor potential cation channel, subfamily M, member 2: TRPM2 ) play roles in preeclampsia with foetal growth restriction23242526272829303132 (Table 1). Likewise, among the 112 target genes up-regulated over 2-fold by the miR-518b mimic (Supplementary Table S2), four genes [hemopexin: HPX , serpin peptidase inhibitor, clade B (ovalbumin), member 2: SERPINB2 , lipoprotein, Lp(a): LPA , and tumour necrosis factor superfamily, member 10: TNFSF10 ] show involvement in preeclampsia35363738, and two genes (CD69 molecule: CD69 and stanniocalcin 1: STC1 ) are involved in preeclampsia with foetal growth restriction333439 (Table 1).…”

“…miR-518b seems to control multiple target genes located on various chromosomes. Interestingly, some miR-518b target genes were previously demonstrated to associate with preeclampsia (e.g., TH and HSD3B1 for down-regulated genes, and HPX, SERPINB2, LPA and TNFSF10 for up-regulated genes)20212235363738 and with preeclampsia with foetal growth restriction (e.g., EDNRA, AGER, WNT2, C9 , and TRPM2 for down-regulated genes, and CD69 and STC1 for up-regulated genes)23242526272829303132333439. However, further experiments are needed to demonstrate a causal relationship between the expression of pregnancy-associated miRNAs and pregnancy-related disorders.…”

Micro- and Nano-vesicles from First Trimester Human Placentae Carry Flt-1 and Levels Are Increased in Severe Preeclampsia

“…This clearly demonstrates that placental EVs carry more than one “danger signal”/toxin that can affect maternal endothelial cells. For example, we have recently reported that PE macro-vesicles carry increased levels of IL-1β and HMGB1 that can act in distinct pathways to Flt-1 to cause endothelial cell activation (27, 51). Similarly, none of the vesicle fractions from mild preeclamptic placentae contained elevated levels of Flt-1, yet all fractions of PE EVs (regardless of the severity of disease) caused endothelial cell activation.…”

Emerging Treatment Models in Rheumatology: Antiphospholipid Syndrome and Pregnancy: Pathogenesis to Translation

“…32 APL, internalized by the syncytiotrophoblast, disrupt mitochondria triggering aberrant cell death that leads to the shedding of dangerous SNAs that activate the maternal vasculature. 33 Exosomes (small extracellular vesicles) released by aPL-exposed extravillous trophoblasts contain elevated levels of the TLR8-activator, miR146a-3p. 30 Furthermore, uptake of trophoblast-derived vesicles by endothelial cells changes the transcriptome and proteome of the maternal vasculature.…”