Cytosolic Double-Stranded DNA Induces Nonnecroptotic Programmed Cell Death in Trophoblasts via IFI16

Chu, Xiao; Chen, Wei; Li, Ning; Hu, Xiao-Zhu; Du, Cheng; Yu, Shui-Xing; Zhou, Min; Zhang, Xiaojing; Jiang, Guimei; Wang, Han; Deng, Xuming; Yang, Yongjun

doi:10.1093/infdis/jiu272

Cited by 15 publications

(22 citation statements)

References 50 publications

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“…27 In contrast, our in vitro data using primary trophoblasts and choriocarcinoma JEG3 cells convincingly demonstrate that trophoblast cells are susceptible to necroptosis under conditions characterized by CER accumulation and caspase inactivation. Hence, trophoblasts may utilize necroptosis as a means of cell death, but this is dependent on the specific pro-death stimuli.…”

Section: Discussionmentioning

confidence: 54%

Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis

et al. 2017

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Preeclampsia, a serious hypertensive disorder of pregnancy, is characterized by elevated ceramide (CER) content that is responsible for heightened trophoblast cell death rates via apoptosis and autophagy. Whether trophoblast cells undergo necroptosis, a newly characterized form of regulated necrosis, and the potential role of CER in this process remain to be established. Herein, we report that exposure of both JEG3 cells and primary isolated cytotrophoblasts to C16:0 CER in conjunction with a caspase-8 inhibitor (Q-VD-OPh) promoted necroptotic cell death, as evidenced by increased expression and association of receptor-interacting protein kinases RIP1 and RIP3, as well as phosphorylation of mixed lineage kinase domain-like (MLKL) protein. MLKL activation and oligomerization could be abrogated by pretreatment with the necroptosis inhibitor necrostatin-1 (Nec-1). CER+Q-VD-OPH-treated primary trophoblasts displayed striking necrotic morphology along with disrupted fusion processes as evidenced by maintenance of E-cadherin-stained membrane boundaries and reduced glial cell missing-1 expression, but these events were effectively reversed using Nec-1. Of clinical relevance, we established an increased susceptibility to necroptotic cell death in preeclamptic placentae relative to normotensive controls. In preeclampsia, increased necrosome (RIP1/RIP3) protein levels, as well as MLKL activation and oligomerization associated with necrotic cytotrophoblast morphology. In addition, caspase-8 activity was reduced in severe early-onset preeclampsia cases. This study is the first to report that trophoblast cells undergo CER-induced necroptotic cell death, thereby contributing to the increased placental dysfunction and cell death found in preeclampsia.

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Section: Discussionmentioning

confidence: 54%

Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis

et al. 2017

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“…Listeria spp. induces cell death in infected human trophoblast [15, 35] as well as in other type cells [12], but Listeria -induced host cell death is observed at later time points of infection.…”

Section: Discussionmentioning

confidence: 99%

Comparative experimental infection of Listeria monocytogenes and Listeria ivanovii in bovine trophoblasts

et al. 2017

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Listeria monocytogenes is a Gram-positive, facultative intracellular and invasive bacterium that has tropism to the placenta, and causes fetal morbidity and mortality in several mammalian species. While infection with L. monocytogenes and L. ivanovii are known as important causes of abortion and reproductive failure in cattle, the pathogenesis of maternal-fetal listeriosis in this species is poorly known. This study used the bovine chorioallantoic membrane explant model to investigate the kinetics of L. monocytogenes, L. ivanovii, and L. innocua infections in bovine trophoblastic cells for up to 8 h post infection. L. monocytogenes and L. ivanovii were able to invade and multiply in trophoblastic cells without causing cell death or inducing expression of pro-inflammatory genes. Although L. innocua was unable to multiply in bovine trophoblastic cells, it induced transcription of the pro-inflammatory mediator CXCL6. This study demonstrated for the first time the susceptibility of bovine trophoblastic cells to L. monocytogenes and L. ivanovii infection.

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“…It is also possible that elevated expression of IFI16 in term placentas was associated with non-necroptotic programmed cell death [49]. Post-transcriptional or post-translational modifications, such as phosphorylation and ubiquitination, may be the reasons for differences in protein production with the corresponding mRNA level in tissue.…”

Section: Discussionmentioning

confidence: 99%

Enhanced expression of IFI16 and RIG-I in human third-trimester placentas following HSV-1 infection

Jabłońska

Studzińska

Suski

et al. 2018

Clinical and Experimental Immunology

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The innate immune response in the placenta depends on the ability of maternal immune cells and fetal trophoblast cells to detect and eliminate invading pathogens through germline-encoded pattern recognition receptors (PRRs). In the present study, we analysed the transcripts and protein expression of interferon (IFN)-inducible protein (IFI)16, melanoma differentiation-associated protein 5 (MDA5), RIG-I-like receptor (RIG-I) and Toll-like receptor (TLR)-3 in third-trimester human placentas and investigated cytokine profiles generated during herpes simplex type 1 (HSV-1) infection. Decidual and chorionic villous biopsies (38-42 weeks of gestation) were obtained from healthy women immediately after a caesarean section. The expression of the DDX58 (RIG-I), IFIH1 (MDA5), IFI16 and TLR3 transcripts was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Extracellular cytokine and PRRs levels were then quantified by enzyme-linked immunosorbent assays (ELISAs). All examined PRRs genes, including DDX58, IFIH1, IFI16 and TLR3, were expressed constitutively at the mRNA and protein levels in the placental biopsies. The concentration of the IFI16 protein was increased in HSV-1-infected decidual and chorionic villous explants compared to those of mock-infected tissues (P = 0·029). Higher protein expression levels of RIG-I in both the maternal and fetal parts of the placenta were found (P = 0·009 and P = 0·004, respectively). In addition, increased production of IFN-β by HSV-1-infected tissues was noticed (P = 0·004 for decidua, P = 0·032 for chorionic villi). No significant differences in the IFN-α, interleukin (IL)-6 and IL-8 levels were found. These results showed that HSV-1 infection can enhance the expression of IFI16 and RIG-I proteins in the human term placenta.

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Cytosolic Double-Stranded DNA Induces Nonnecroptotic Programmed Cell Death in Trophoblasts via IFI16

Cited by 15 publications

References 50 publications

Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis

Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis

Comparative experimental infection of Listeria monocytogenes and Listeria ivanovii in bovine trophoblasts

Enhanced expression of IFI16 and RIG-I in human third-trimester placentas following HSV-1 infection

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