Effect of Macrophage Migration Inhibitory Factor (MIF) in Human Placental Explants Infected with Toxoplasma gondii Depends on Gestational Age

Gomes, Angélica de Oliveira; Silva, Deise Aparecida de Oliveira; Silva, Neide Maria; Barbosa, Bellisa de Freitas; Franco, Priscila Silva; Angeloni, Mariana Bodini; Fermino, Marise Lopes; Roque-Barreira, Maria Cristina; Bechi, Nicoletta; Paulesu, Luana; Santos, Mário Coutinho dos; Mineo, José Roberto; Ferro, Eloísa Amália Vieira

doi:10.1016/j.ajpath.2011.02.005

Cited by 51 publications

(66 citation statements)

References 54 publications

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“…MIF may play an essential role as an autocrine/paracrine mediator in placental infection. 23, 30 In this context, our finding that expression of CD74 is downregulated in preeclampsia suggests a disturbance of the normally balanced immune response to antigens in the preeclamptic placenta. MIF expression and concentrations were described in pregnancy and preeclampsia by Cardaropoli et al 31 Only in serum of preeclamptic women accompanied by fetal growth restriction they found significantly higher MIF levels compared to controls.…”

Section: Discussionmentioning

confidence: 84%

“…In human placental explants infected by Toxoplasma gondii , a model for induction and suppression of infection, CD74 was detected in first but not third trimester trophoblasts, as well as in Hofbauer cells. 30 However, colocalization of CD74 with a marker like CD163 for macrophages or CK7 for trophoblast was not performed. The expression of CD74 in general was higher in first trimester explants.…”

Section: Discussionmentioning

confidence: 99%

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CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia

et al. 2016

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RATIONALE We hypothesized that Cluster of differentiation 74 (CD74) downregulation of placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia. OBJECTIVE Preeclamptic pregnancies feature hypertension, proteinuria and placental anomalies. Feto-placental macrophages regulate villous trophoblast differentiation during placental development. Disturbance of this well-balanced regulation can lead to pathological pregnancies. METHODS AND RESULTS We performed whole genome expression analysis of placental tissue. CD74 was one of the most downregulated genes in placentas from preeclamptic women. By RT-PCR, we confirmed this finding in early onset (<34 gestational week, n=26) and late onset (≥34 gestational week, n=24) samples from preeclamptic women, compared to healthy pregnant controls (n=28). CD74 protein levels were analyzed by Western blot and flow cytometry. We identified placental macrophages to express CD74 by immunofluorescence, flow cytometry and RT-PCR. CD74-positive macrophages were significantly reduced in preeclamptic placentas compared to controls. CD74-silenced macrophages showed that the adhesion molecules ALCAM, ICAM4, and Syndecan-2, as well as macrophage adhesion to trophoblasts were diminished. Naïve and activated macrophages lacking CD74 showed a shift towards a pro-inflammatory signature with an increased secretion of TNFα, CCL5, and MCP-1, when co-cultured with trophoblasts compared to control macrophages. Trophoblasts stimulated by these factors express more CYP2J2, sFlt1, TNFα and IL-8. CD74-knockout mice showed disturbed placental morphology, reduced junctional zone, smaller placentas and impaired spiral artery remodeling with fetal growth restriction. CONCLUSIONS CD74 downregulation in placental macrophages is present in preeclampsia. CD74 downregulation leads to altered macrophage activation towards a pro-inflammatory signature and a disturbed crosstalk with trophoblasts.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia

et al. 2016

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“…Sections with 4 μm were placed on glass slides and subjected to immunohistochemical analysis (de Oliveira Gomes et al, 2011; Castro-Filice et al, 2014). Briefly, for antigenic retrieval, sections were covered with citric acid pH 6.0 for 5 min in a microwave.…”

Section: Methodsmentioning

confidence: 99%

Enrofloxacin and Toltrazuril Are Able to Reduce Toxoplasma gondii Growth in Human BeWo Trophoblastic Cells and Villous Explants from Human Third Trimester Pregnancy

Silva

Gomes

Franco

et al. 2017

Front. Cell. Infect. Microbiol.

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Classical treatment for congenital toxoplasmosis is based on combination of sulfadiazine and pyrimethamine plus folinic acid. Due to teratogenic effects and bone marrow suppression caused by pyrimethamine, the establishment of new therapeutic strategies is indispensable to minimize the side effects and improve the control of infection. Previous studies demonstrated that enrofloxacin and toltrazuril reduced the incidence of Neospora caninum and Toxoplasma gondii infection. The aim of the present study was to evaluate the efficacy of enrofloxacin and toltrazuril in the control of T. gondii infection in human trophoblast cells (BeWo line) and in human villous explants from the third trimester. BeWo cells and villous were treated with several concentrations of enrofloxacin, toltrazuril, sulfadiazine, pyrimethamine, or combination of sulfadiazine+pyrimethamine, and the cellular or tissue viability was verified. Next, BeWo cells were infected by T. gondii (2F1 clone or the ME49 strain), whereas villous samples were only infected by the 2F1 clone. Then, infected cells and villous were treated with all antibiotics and the T. gondii intracellular proliferation as well as the cytokine production were analyzed. Finally, we evaluated the direct effect of enrofloxacin and toltrazuril in tachyzoites to verify possible changes in parasite structure. Enrofloxacin and toltrazuril did not decrease the viability of cells and villous in lower concentrations. Both drugs were able to significantly reduce the parasite intracellular proliferation in BeWo cells and villous explants when compared to untreated conditions. Regardless of the T. gondii strain, BeWo cells infected and treated with enrofloxacin or toltrazuril induced high levels of IL-6 and MIF. In villous explants, enrofloxacin induced high MIF production. Finally, the drugs increased the number of unviable parasites and triggered damage to tachyzoite structure. Taken together, it can be concluded that enrofloxacin and toltrazuril are able to control T. gondii infection in BeWo cells and villous explants, probably by a direct action on the host cells and parasites, which leads to modifications of cytokine release and tachyzoite structure.

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“…Recently, de Oliveira Gomes et al compared first-and thirdtrimester human placental explants infected with type I (RH) T. gondii (18). Cultured placentas past gestational week 8 do not invade or develop EVT; explants in that study were cultured in suspension and thus comprise only floating villi, often with "open" arms exposing fetal stroma to the surrounding media (48).…”

Section: Discussionmentioning

confidence: 99%

Tissue Barriers of the Human Placenta to Infection with Toxoplasma gondii

et al. 2012

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Toxoplasma gondii is a ubiquitous, obligate intracellular parasite capable of crossing the placenta to cause spontaneous abortion, preterm labor, or significant disease in the surviving neonate. Exploration of the cellular and histological components of the placental barrier is in its infancy, and both how and where T. gondii breaches it are unknown. The human placenta presents two anatomical interfaces between maternal cells and fetal cells (trophoblasts): (i) the villous region where maternal blood bathes syncytialized trophoblasts for nutrient exchange and (ii) the maternal decidua, where mononuclear, extravillous trophoblasts anchor the villous region to the uterus. Using first-trimester human placental explants, we demonstrate that the latter site is significantly more vulnerable to infection, despite presenting a vastly smaller surface. This is consistent with past findings concerning two vertically transmitted viruses and one bacterium. We further explore whether three genetically distinct T. gondii types (I, II, and III) are capable of preferential placental infection and survival in this model. We find no difference in these strains' ability to infect placental explants; however, slightly slower growth is evident in type II (Prugniaud [Pru]) parasites relative to other cell types, although this did not quite achieve statistical significance.T oxoplasma gondii is a ubiquitous parasite of human and veterinary medical importance. This obligate, intracellular protozoan undergoes the sexual portion of its life cycle in cats, the sole definitive host; it also has an asexual life cycle in a broad range of warm-blooded intermediate hosts, most significantly rodents, livestock, and humans. The main modes of transmission are therefore ingestion of oocysts shed in cat feces or of tissue cysts in undercooked meat from intermediate hosts. T. gondii is capable of crossing the blood-brain, blood-ocular, and maternal-fetal barriers. Thus, the vertical route from mother to fetus represents an additional mode of transmission. Fetal infection can cause spontaneous abortion, preterm labor, or significant neurological and ocular sequelae in the surviving offspring.Primary maternal infection during pregnancy is responsible for almost all fetal infection and its frequency depends on human seroprevalence rates that range from ϳ10 to 80% across nations (53). Prenatal testing for toxoplasmosis is routinely offered in many European countries, and drug therapy with spiramycin is prescribed after the diagnosis of maternal infection in order to prevent mother-to-child transmission (19). However, whether prenatal treatment has any effect on vertical transmission is unclear from the results of a systematic review of cohort studies because of numerous biases in the way these studies were designed (65). Randomized controlled clinical trials are needed to obtain evidence for the benefit of prenatal treatment.The mechanisms by which T. gondii infects the placenta and crosses from mother to fetus are poorly understood and experimentally co...

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Effect of Macrophage Migration Inhibitory Factor (MIF) in Human Placental Explants Infected with Toxoplasma gondii Depends on Gestational Age

Cited by 51 publications

References 54 publications

CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia

CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia

Enrofloxacin and Toltrazuril Are Able to Reduce Toxoplasma gondii Growth in Human BeWo Trophoblastic Cells and Villous Explants from Human Third Trimester Pregnancy

Tissue Barriers of the Human Placenta to Infection with Toxoplasma gondii

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