A Placental Protective Role for Trophoblast-Derived TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Bai, Xilian; Williams, J.; Greenwood, Susan; Baker, Philip N.; Aplin, John D.; Crocker, Ian

doi:10.1016/j.placenta.2009.07.006

Cited by 39 publications

(43 citation statements)

References 40 publications

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“…Previously proposed function as a protein repairing syncytial damage and maintaining the placental barrier integrity could not be confirmed. Instead, a similar function for TRAIL as for FasL as a contributor to immune privilege was suggested, and an intracellular compartmental restriction of TRAIL expression in the placenta similar to that of FasL was assumed but not documented (18). In line with this assumption, we show that TRAIL is restricted to STB's endosomal compartment and expressed and released on exosome-like microvesicles.…”

Section: Discussionsupporting

confidence: 49%

“…In line with this assumption, we show that TRAIL is restricted to STB's endosomal compartment and expressed and released on exosome-like microvesicles. The previously described cell membrane expression on CTB and STB (18) could not be confirmed despite detailed IEM analyses. Similar results of exosomal TRAIL and FasL expression have been shown in other cells and sites such as dendritic and T cells (5, 48, 49), melanoma, and ovarian cancer cells (50,51) and in joint fluid of rheumatoid arthritis patients (52).…”

Section: Discussionmentioning

confidence: 60%

“…Initially, it was found that both forms were equally effective (44), whereas later reports singled out membrane-bound TRAIL as the molecular form preferably inducing cell death (45)(46)(47). Recently, it was reported that TRAIL protein in STB cultures could be at least partly localized to the cytoplasm (18). Previously proposed function as a protein repairing syncytial damage and maintaining the placental barrier integrity could not be confirmed.…”

Section: Discussionmentioning

confidence: 99%

“…Both FasL and TRAIL were found to be constitutively expressed by the placenta and proposed as cooperating players for inducing apoptosis in activated lymphocytes (16)(17)(18) that might pose a potential threat to the fetus. As stated above, membrane-bound Fas ligand (mFasL) but not soluble FasL (sFasL) promotes apoptosis of Fas-bearing cells (19,20).…”

mentioning

confidence: 99%

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Exosomes Secreted by Human Placenta Carry Functional Fas Ligand and TRAIL Molecules and Convey Apoptosis in Activated Immune Cells, Suggesting Exosome-Mediated Immune Privilege of the Fetus

Stenqvist

Nagaeva

Baranov

et al. 2013

The Journal of Immunology

250

238

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Apoptosis is crucially important in mediating immune privilege of the fetus during pregnancy. We investigated the expression and in vitro apoptotic activity of two physiologically relevant death messengers, the TNF family members Fas ligand (FasL) and TRAIL in human early and term placentas. Both molecules were intracellularly expressed, confined to the late endosomal compartment of the syncytiotrophoblast, and tightly associated to the generation and secretion of placental exosomes. Using immunoelectron microscopy, we show that FasL and TRAIL are expressed on the limiting membrane of multivesicular bodies where, by membrane invagination, intraluminal microvesicles carrying membranal bioactive FasL and TRAIL are formed and released in the extracellular space as exosomes. Analyzing exosomes secreted from placental explant cultures, to our knowledge, we demonstrate for the first time that FasL and TRAIL are clustered on the exosomal membrane as oligomerized aggregates ready to form death-inducing signaling complex. Consistently, placental FasL- and TRAIL-carrying exosomes triggered apoptosis in Jurkat T cells and activated PBMC in a dose-dependent manner. Limiting the expression of functional FasL and TRAIL to exosomes comprise a dual benefit: 1) storage of exosomal FasL and TRAIL in multivesicular bodies is protected from proteolytic cleavage and 2) upon secretion, delivery of preformed membranal death molecules by exosomes rapidly triggers apoptosis. Our results suggest that bioactive FasL- and TRAIL-carrying exosomes, able to convey apoptosis, are secreted by the placenta and tie up the immunomodulatory and protective role of human placenta to its exosome-secreting ability.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Exosomes Secreted by Human Placenta Carry Functional Fas Ligand and TRAIL Molecules and Convey Apoptosis in Activated Immune Cells, Suggesting Exosome-Mediated Immune Privilege of the Fetus

Stenqvist

Nagaeva

Baranov

et al. 2013

The Journal of Immunology

250

238

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“…In addition to a signal peptide, DR5 also contains a nuclear localization sequence (NLS), and transport into nuclei is likely to be mediated by this motif. Although the function of DR5 in the nucleus is not known, it is possible that DR5 can modulate transcription because DR5 over-expression was reported to lead to activation of transcription factor NF-jB and inhibition of neuroapoptosis (Bai et al 2009;Leithner et al 2009).…”

Section: Dr5 Expression In the Nucleusmentioning

confidence: 99%

Death Receptor 5 and Neuroproliferation

Niu

Zang

et al. 2011

Cell Mol Neurobiol

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Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand is a member of the tumor necrosis factor superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). However, DR5 is also expressed in the developing CNS where it appears to play a role unrelated to apoptosis, and instead may be involved in the regulation of neurogenesis. We report on the distribution of DR5 expression in mouse hippocampus, cerebellum, and rostral migratory stream (RMS) of olfactory bulb from embryonic (E) day 16 (E16) to postnatal (P) day (P180). At E16, DR5-positive cells were distributed widely in embryonic hippocampus with strong immunostaining in the developing dentate gyrus. In newborn hippocampus, DR5-positive cells were predominantly located in proliferative zones, such as dentate gyrus, subventricular zone, and RMS. After postnatal day 7 (P7), the number of DR5-positive cells decreased, and cells with intense fluorescence were primarily restricted to the subgranular layer (SGL), although the granular cell layer showed weak fluorescence. After P30, only few DR5-positive cells were found in SGL, and mature granule cells were negative for DR5 expression. To address whether DR5 expression is a restricted to progenitor cells and newborn neurons, we performed 5-bromo-deoxyuridine labeling. We report that proliferative cells in the SGL selectively express DR5, with lower levels of expression in cells positive for doublecortin, a marker of newborn neurons. In addition, the stem cells in intestine, cerebellum, and RMS were also demonstrated to be DR5-positive. In the meantime, in cerebellum, DR5-positive cells were also positive for glial fibrillary acidic protein, a marker of proliferative Bergmann cells. We conclude that DR5 is selectively expressed by neuroprogenitor cells and newborn neurons, suggesting that the DR5 death receptor is likely to play a key role in neuroproliferation and differentiation.

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Pre‐eclampsia: fitting together the placental, immune and cardiovascular pieces

James

Whitley

Cartwright

2010

The Journal of Pathology

195

117

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The success of pregnancy is a result of countless ongoing interactions between the placenta and the maternal immune and cardiovascular systems. Pre-eclampsia is a serious pregnancy complication that arises from multiple potential aberrations in these systems. The pathophysiology of pre-eclampsia is established in the first trimester of pregnancy, when a range of deficiencies in placentation affect the key process of spiral artery remodelling. As pregnancy progresses to the third trimester, inadequate spiral artery remodelling along with multiple haemodynamic, placental and maternal factors converge to activate the maternal immune and cardiovascular systems, events which may in part result from increased shedding of placental debris. As we understand more about the pathophysiology of pre-eclampsia, it is becoming clear that the development of early-and late-onset pre-eclampsia, as well as intrauterine growth restriction (IUGR), does not necessarily arise from the same underlying pathology.

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A Placental Protective Role for Trophoblast-Derived TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Cited by 39 publications

References 40 publications

Exosomes Secreted by Human Placenta Carry Functional Fas Ligand and TRAIL Molecules and Convey Apoptosis in Activated Immune Cells, Suggesting Exosome-Mediated Immune Privilege of the Fetus

Exosomes Secreted by Human Placenta Carry Functional Fas Ligand and TRAIL Molecules and Convey Apoptosis in Activated Immune Cells, Suggesting Exosome-Mediated Immune Privilege of the Fetus

Death Receptor 5 and Neuroproliferation

Pre‐eclampsia: fitting together the placental, immune and cardiovascular pieces

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