Cytomegalovirus Infection Triggers the Secretion of the PPARγ Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures

Leghmar, Kaoutar; Cenac, Nicolas; Rolland, Maude; Martin, Hélène; Rauwel, Benjamin; Bertrand‐Michel, Justine; Faouder, Pauline Le; Bénard, Mélinda; Casper, Charlotte; Davrinche, Christian; Fournier, Thierry; Chavanas, Stéphane

doi:10.1371/journal.pone.0132627

Cited by 21 publications

(25 citation statements)

References 41 publications

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“…Interestingly, during HCMV virion assembly, cellular cPLA2 is packaged into the viral particle and remains within the tegument of the virions, as an “onboarded” cell-derived cPLA2 which is required for infectivity [ 23 ]. It has been shown that this cell-derived cPLA2 can be inhibited by treatment of the viral inoculum by the specific cPLA 2 inhibitor methyl arachidonyl fluorophosphonate (MAFP) before infection [ 23 , 24 ]. Accordingly, we observed that treatment of the inoculum by 50 μM MAFP abolished IE expression in NSCs ( Fig 6A ).…”

Section: Resultsmentioning

confidence: 99%

“…We have recently reported that 13-HODE and 15-HETE were the PPARγ agonists secreted by cytotrophoblasts and placenta explants infected by HCMV. In this case, however, no 9-HODE changes were detected [ 24 ]. This suggests tissue specificity in the response to HCMV infection with regard to fatty acids metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Cell-derived, virion-packaged cPLA 2 was inactivated as described elsewhere [ 24 ]. Viral suspensions were incubated in a volume of 1 ml for 1 h at room temperature in the presence of 50 μM methyl arachidonyl fluorophosphonate (MAFP; Sigma), ultracentrifuged at 100,000 × g for 30 min at 4°C, washed twice with phosphate-buffered saline (PBS; Life Technologies) and diluted in culture medium.…”

Section: Methodsmentioning

confidence: 99%

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PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells

Rolland

Sellier

et al. 2016

PLoS Pathog

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Congenital infection by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae of the central nervous system, including sensorineural deafness, cerebral palsies or devastating neurodevelopmental abnormalities (0.1% of all births). To gain insight on the impact of HCMV on neuronal development, we used both neural stem cells from human embryonic stem cells (NSC) and brain sections from infected fetuses and investigated the outcomes of infection on Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a transcription factor critical in the developing brain. We observed that HCMV infection dramatically impaired the rate of neuronogenesis and strongly increased PPARγ levels and activity. Consistent with these findings, levels of 9-hydroxyoctadecadienoic acid (9-HODE), a known PPARγ agonist, were significantly increased in infected NSCs. Likewise, exposure of uninfected NSCs to 9-HODE recapitulated the effect of infection on PPARγ activity. It also increased the rate of cells expressing the IE antigen in HCMV-infected NSCs. Further, we demonstrated that (1) pharmacological activation of ectopically expressed PPARγ was sufficient to induce impaired neuronogenesis of uninfected NSCs, (2) treatment of uninfected NSCs with 9-HODE impaired NSC differentiation and (3) treatment of HCMV-infected NSCs with the PPARγ inhibitor T0070907 restored a normal rate of differentiation. The role of PPARγ in the disease phenotype was strongly supported by the immunodetection of nuclear PPARγ in brain germinative zones of congenitally infected fetuses (N = 20), but not in control samples. Altogether, our findings reveal a key role for PPARγ in neurogenesis and in the pathophysiology of HCMV congenital infection. They also pave the way to the identification of PPARγ gene targets in the infected brain.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells

Rolland

Sellier

et al. 2016

PLoS Pathog

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“…Persistence of a moderate to large ductus arteriosus following birth is a risk factor for BPD. Furthermore, the previously mentioned hydroxy acids and ketones are associated with placental signaling via activation of peroxisome proliferator-activated receptor (PPAR)␥ (10,35,61). Specifically, 9-and 13-HODE, and 13-oxo-ODE are putative ligands of PPAR␥, the expression of which, in the placenta, has been shown to be vital for proper cardiac tissue development (3) and implicated in the regulation of PH development (55).…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord blood metabolomics reveal distinct signatures of dyslipidemia prior to bronchopulmonary dysplasia and pulmonary hypertension

Frano

Fahrmann

Pedersen

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension (PH) is a common consequence of bronchopulmonary dysplasia (BPD) and remains a primary contributor to increased morbidity and mortality among preterm infants. Unfortunately, at the present time there are no reliable early predictive markers for BPD-associated PH. Considering its health consequences, understanding in utero perturbations that lead to the development of BPD and BPD-associated PH and identifying early predictive markers is of utmost importance. As part of the discovery phase, we applied a multi-platform metabolomics approach consisting of untargeted and targeted methodologies to screen for metabolic perturbations in umbilical cord blood (UCB) plasma from preterm infants that did (n=21; cases) or did not (n=21; controls) develop subsequent PH. A total of 1,656 features were detected of which 407 were annotated by metabolite structures. PH-associated metabolic perturbations were characterized by reductions in major choline-containing phospholipids such as phosphatidycholines (PCs) and sphingomyelins, indicating altered lipid metabolism. The reduction in UCB abundances of major choline-containing phospholipids was confirmed in an independent validation cohort consisting of UCB plasmas from 10 cases and 10 controls matched for gestational age and BPD status. Sub-analyses in the discovery cohort indicated that elevations in the oxylipins PGE1, PGE2, PGF2a, 9- and 13-HOTE, 9- and 13-HODE, and 9- and 13-KODE were positively associated with BPD presence and severity. This expansive evaluation of cord blood plasma identifies compounds reflecting dyslipidemia and suggest altered metabolite provision associated with metabolic immaturity that differentiate subjects both by BPD severity and PH development.

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“…Incidentally, we had previously showed that PPARg activity is mandatory for HCMV replication and is dramatically enhanced in cytotrophoblasts and placentae infected by HCMV. 20 Therefore, we investigated the outcomes of HCMV infection on PPARg in NSCs.…”

Section: Role Of Pparg In Hcmv Neuropathymentioning

confidence: 99%

Peroxisome proliferator-activated receptor γ (PPARγ) activation: A key determinant of neuropathogeny during congenital infection by cytomegalovirus

Chavanas

2016

Neurogenesis

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Congenital infection by human cytomegalovirus (HCMV) might result in permanent neurological sequelae, including sensorineural deafness, cerebral palsies or devastating neurodevelopmental abnormalities. We recently disclosed that Peroxisome ProliferatorActivated Receptor gamma (PPARg), a transcription factor of the nuclear receptor superfamily, is a key determinant of HCMV pathogenesis in developing brain. Using neural stem cells from human embryonic stem cells, we showed that HCMV infection strongly increases levels and activity of PPARg in NSCs. Further in vitro experiments showed that PPARg activity inhibits the neuronogenic differentiation of NSCs into neurons. Consistently, increased PPARg expression was found in brain section of fetuses infected by HCMV, but not in uninfected controls. In this commentary, we summarize and discuss our findings and the new insights they provide on the neuropathogenesis of HCMV congenital infection.

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Cytomegalovirus Infection Triggers the Secretion of the PPARγ Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures

Cited by 21 publications

References 41 publications

PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells

PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells

Umbilical cord blood metabolomics reveal distinct signatures of dyslipidemia prior to bronchopulmonary dysplasia and pulmonary hypertension

Peroxisome proliferator-activated receptor γ (PPARγ) activation: A key determinant of neuropathogeny during congenital infection by cytomegalovirus

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