Heme-mediated apoptosis and fusion damage in BeWo trophoblast cells

Abstract

Placental malaria (PM) is a complication associated with malaria infection during pregnancy that often leads to abortion, premature delivery, intrauterine growth restriction and low birth weight. Increased levels of circulating free heme, a by-product of Plasmodium-damaged erythrocytes, is a major contributor to inflammation, tissue damage and loss of blood brain barrier integrity associated with fatal experimental cerebral malaria. However, the role of heme in PM remains unknown. Proliferation and apoptosis of trophoblasts and fusion of the mononucleated state to the syncytial state are of major importance to a successful pregnancy. In the present study, we examined the effects of heme on the viability and fusion of a trophoblast-derived cell line (BeWo). Results indicate that heme induces apoptosis in BeWo cells by activation of the STAT3/caspase-3/PARP signaling pathway. In the presence of forskolin, which triggers trophoblast fusion, heme inhibits BeWo cell fusion through activation of STAT3. Understanding the effects of free plasma heme in pregnant women either due to malaria, sickle cell disease or other hemolytic diseases, will enable identification of high-risk women and may lead to discovery of new drug targets against associated adverse pregnancy outcome.

Fetal and Maternal Innate Immunity Receptors Have Opposing Effects on the Severity of Experimental Malaria in Pregnancy: Beneficial Roles for Fetus-Derived Toll-Like Receptor 4 and Type I Interferon Receptor 1

“…Evidence that in vitro trophoblast responses may play a role in enhancing the inflammatory milieu and placental tissue damage during MiP was reported previously ( 65 – 69 ). Additionally, it has been shown that trophoblasts express an array of innate immunity receptors, including TLRs and NOD-like receptors ( 70 – 74 ), and mediate interferon production ( 75 ), suggesting that these cells, located at the maternal-fetal interface, are equipped to sense and respond to innate immunity triggers.…”

A novel approach to wildlife transcriptomics provides evidence of disease‐mediated differential expression and changes to the microbiome of amphibian populations

“…The highest fold change of any gene up‐regulated in positive disease history populations was associated with ATP‐binding cassette transporter 10, which has been shown to be essential to the formation of haeme in mice (Yamamoto et al., ). Haeme, when liberated from larger proteins (such as haemoglobin), is known to play a key role in cellular damage caused by pro‐inflammatory pathogens (Liu, Hassana, & Stiles, ; Yamamoto et al., ). A host inflammatory response gene (NLR family pyrin domain containing 13; NLRP13) was also up‐regulated in positive disease history populations.…”

“…The highest fold change of any gene up-regulated in positive disease history populations was associated with ATP-binding cassette transporter 10, which has been shown to be essential to the formation of haeme in mice(Yamamoto et al, 2014). Haeme, when liberated from larger proteins (such as haemoglobin), is known to play a key role in cellular damage caused by pro-inflammatory pathogens(Liu, Hassana, & Stiles, 2016;Yamamoto et al, 2014). A host inflammatory response gene (NLR family pyrin domain containing 13; NLRP13) was also up-regulated in positive disease history populations.Following initial inflammatory and innate immune response, clearance of ranaviral infection in X. laevis is dependent on the adultF I G U R E 3 Euclidean distance heat maps showing between population distances in transcript profiles; Left-transcript profile distances based on the whole of our assembled transcriptome (502,961 transcripts) and Right-transcript distances based on transcripts identified as differentially expressed between populations of disease history classes (407 transcripts).…”

Integrated Proteomics Reveals Apoptosis-related Mechanisms Associated with Placental Malaria*

“…Recently, Liu et al (60), proposed that hemozoin, a pigment produced by the Plasmodium parasites by the degradation of hemoglobin, promotes apoptosis in trophoblast cells by activating the STAT3/caspase-3/PARP signaling pathway. Additionally, in mosquito cells, hemozoin was shown to play a role inducing NO synthase expression, as well as AKT and ERK activation (61) and, in macrophages, hemozoin induces a powerful synergistic effect on the IFN-gamma-inducible NO generation via ERK-and NF-kappaB-dependent pathways (62).…”