IL-1β and TGF-β weaken the placental barrier through destruction of tight junctions: An in vivo and in vitro study

Tossetta, Giovanni; Paolinelli, Francesca; Avellini, Chiara; Salvolini, Eleonora; Ciarmela, Pasquapina; Lorenzi, Teresa; Emanuelli, Monica; Toti, Paolo; Giuliante, Rachela; Gesuita, Rosaria; Crescimanno, Caterina; Voltolini, Chiara; Primio, Roberto Di; Petraglia, Felice; Castellucci, Mario; Marzioni, Daniela

doi:10.1016/j.placenta.2014.03.016

Cited by 48 publications

(42 citation statements)

References 41 publications

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“…Furthermore, it was found in animal studies that LPS could compromise placental barrier integrity and affect its permeability . It was also observed in the in vitro study that inflammatory cytokines could weaken the placental barrier through destruction of tight junctions at trophoblastic and endothelial cells . Therefore, although we failed to find out the source of elevated MS‐AFP, the lower level of fetal serum AFP in LPS‐treated rats might serve as an indirect evidence that increased fetal‐maternal AFP transfer through impaired placental barrier might be the cause of elevated MS‐AFP.…”

Section: Discussionmentioning

confidence: 78%

A rat model of placental inflammation explains the unexplained elevated maternal serum alpha‐fetoprotein associated with adverse pregnancy outcomes

Zhang

Chan

et al. 2019

J of Obstet and Gynaecol

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Aim It has been reported in numerous studies that elevated maternal serum alpha‐fetoprotein (MS‐AFP) is associated with adverse pregnancy outcomes (APO), such as pre‐eclampsia, stillbirth, preterm birth and fetal growth restriction. However, the mechanism linking elevated MS‐AFP and APO is obscure. In this study, we tried to explore the mechanism by using pregnant rats. Methods Lipopolysaccharide (LPS) was used to induce placental inflammation in pregnant rats. Maternal serum and placental inflammatory cytokines and placental morphology were used to assess the level of placental inflammation. The incidences of APO and the levels of MS‐AFP were evaluated. The expressions of alpha‐fetoprotein (AFP) in the related organs and fetal serum AFP levels were detected. Results Compared to saline‐treated pregnant rats, LPS led to elevated maternal serum and placental inflammatory cytokines and a higher rate of placental inflammation. Lipopolysaccharide resulted in the features of APO and at the same time elevated MS‐AFP. Maternal serum alpha‐fetoprotein levels were significantly correlated to the evaluation parameters of APO. Lipopolysaccharide did not increase the expressions of AFP in fetal liver, maternal liver and placenta, but reduced the fetal serum AFP levels. Conclusion The phenomenon that elevated MS‐AFP is associated with APO, which has been reported in human pregnancies, is observed in our rat model. Placental inflammation can be the potential cause linking the two manifestations together. Although the source of elevated MS‐AFP is not identified, fetal blood circulation is suspected. Our study may provide an animal model for the future studies on this subject.

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Section: Discussionmentioning

confidence: 78%

A rat model of placental inflammation explains the unexplained elevated maternal serum alpha‐fetoprotein associated with adverse pregnancy outcomes

Zhang

Chan

et al. 2019

J of Obstet and Gynaecol

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“…In the placenta, tight junction proteins provide a barrier between the mother and fetus in regulating the exchange of materials, and the permeability of the placenta can be altered during inflammation. Chorioamnionitis-induced upregulation of proinflammatory cytokines decreases expression of tight junction proteins in trophoblastic and endothelial cells of the placenta, facilitating infection (Tossetta et al, 2014). Furthermore, co-culture of human umbilical vein endothelial cells with the placental trophoblast cells from women with preeclampsia results in decreased barrier function of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

The placental interleukin-6 signaling controls fetal brain development and behavior

Hsiao

Yan

et al. 2017

Brain, Behavior, and Immunity

206

170

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Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6Rα) in placental trophoblasts (Cyp19-Cre+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/fl mothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced inflammatory responses in the placenta and the fetal brain. Furthermore, behavioral abnormalities and cerebellar neuropathologies observed in MIA control offspring are prevented in Cyp19-Cre+;Il6rafl/fl offspring. Our results demonstrate that IL-6 activation in placenta is required for relaying inflammatory signals to the fetal brain and impacting behaviors and neuropathologies relevant to neurodevelopmental disease.

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“…T cell tolerance and trafficking are regulated by decidual stroma cells in the placenta, providing additional protection from aberrant maternal immunity 51–53 . When challenged with inflammation, the placental barrier function is weakened, allowing T cell infiltration 54 . Indeed, our immunohistochemical results indicate that intrauterine inflammation leads to an increase in CD3 + /CD45 + cells on both maternal and fetal sides of the placenta, with a significant decrease following DNAC but not free NAC treatment (Fig.…”

Section: Discussionmentioning

confidence: 99%

Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury

Lei

Rosenzweig

Mishra

et al. 2017

Sci Rep

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Preterm birth is a major risk factor for adverse neurological outcomes in ex-preterm children, including motor, cognitive, and behavioral disabilities. N-acetyl-L-cysteine therapy has been used in clinical studies; however, it requires doses that cause significant side effects. In this study, we explore the effect of low dose N-acetyl-L-cysteine therapy, delivered using a targeted, systemic, maternal, dendrimer nanoparticle (DNAC), in a mouse model of intrauterine inflammation. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the preterm birth rate and altered placental immune profile with decreased CD8+ T-cell infiltration. Furthermore, we demonstrated that DNAC improved neurobehavioral outcomes and reduced fetal neuroinflammation and long-term microglial activation in offspring. Our study is the first to provide evidence for the role of CD8+ T-cell in the maternal-fetal interface during inflammation and further support the efficacy of DNAC in preventing preterm birth and prematurity-related outcomes.

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IL-1β and TGF-β weaken the placental barrier through destruction of tight junctions: An in vivo and in vitro study

Cited by 48 publications

References 41 publications

A rat model of placental inflammation explains the unexplained elevated maternal serum alpha‐fetoprotein associated with adverse pregnancy outcomes

A rat model of placental inflammation explains the unexplained elevated maternal serum alpha‐fetoprotein associated with adverse pregnancy outcomes

The placental interleukin-6 signaling controls fetal brain development and behavior

Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury

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