Next-generation sequencing reveals IL11 drives preeclampsia by disrupting trophoblast differentiation and activating the placental inflammasome
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PROVIDER: PRJNA797243 | ENA |
REPOSITORIES: ENA
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Project description:Preeclampsia is a life-threatening disorder of pregnancy unique to humans. Interleukin (IL)11 is elevated in serum from pregnancies that subsequently develop early-onset preeclampsia and pharmacological elevation of IL11 in pregnant mice causes the development of preeclampsia-like features (hypertension and proteinuria), however, the mechanism by which IL11 drives preeclampsia-like features is unknown. Using Next-generation sequencing we demonstrate that treatment with PEGylated IL11 (PEGIL11) inhibited placental expression of markers of spongiotrophoblast and syncytiotrophoblast linages and increased placental cathepsin production in wild-type and Asc-/- mice. Function studies showed that IL11 acts via Asc inflammasomes to induce tissue fibrosis and preeclampsia in mice. This study has far-reaching implications on our understanding of the underlying etiology of preeclampsia and the mechanism by which IL11 causes inflammation and fibrosis in many tissues and disease states.
2023-05-09 | GSE193685 | GEO
Project description:IntroductionPreeclampsia is a life-threatening disorder of pregnancy unique to humans. Interleukin (IL)11 is elevated in serum from pregnancies that subsequently develop early-onset preeclampsia and pharmacological elevation of IL11 in pregnant mice causes the development of early-onset preeclampsia-like features (hypertension, proteinuria, and fetal growth restriction). However, the mechanism by which IL11 drives preeclampsia is unknown.MethodPregnant mice were administered PEGylated (PEG)IL11 or control (PEG) from embryonic day (E)10-16 and the effect on inflammasome activation, systolic blood pressure (during gestation and at 50/90 days post-natal), placental development, and fetal/post-natal pup growth measured. RNAseq analysis was performed on E13 placenta. Human 1st trimester placental villi were treated with IL11 and the effect on inflammasome activation and pyroptosis identified by immunohistochemistry and ELISA.ResultPEGIL11 activated the placental inflammasome causing inflammation, fibrosis, and acute and chronic hypertension in wild-type mice. Global and placental-specific loss of the inflammasome adaptor protein Asc and global loss of the Nlrp3 sensor protein prevented PEGIL11-induced fibrosis and hypertension in mice but did not prevent PEGIL11-induced fetal growth restriction or stillbirths. RNA-sequencing and histology identified that PEGIL11 inhibited trophoblast differentiation towards spongiotrophoblast and syncytiotrophoblast lineages in mice and extravillous trophoblast lineages in human placental villi.DiscussionInhibition of ASC/NLRP3 inflammasome activity could prevent IL11-induced inflammation and fibrosis in various disease states including preeclampsia.
| S-EPMC10244672 | biostudies-literature
Project description:Preeclampsia is a severe placenta-related pregnancy disorder that is generally divided into two subtypes named early-onset preeclampsia (onset <34 weeks of gestation), and lateonset preeclampsia (onset ≥34 weeks of gestation), with distinct pathophysiological origins. Both forms of preeclampsia have been associated with maternal systemic inflammation. However, alterations in the placental immune system have been less well characterized. Here, we studied immunological alterations in early- and late-onset preeclampsia placentas using a targeted expression profile approach. RNA was extracted from snap-frozen placenta samples (healthy n=13, early-onset preeclampsia n=13, and late-onset preeclampsia n=6). The expression of 730 immune-related genes from the Pan Cancer Immune Profiling Panel was measured, and the data were analyzed Q10 in the advanced analysis module of nSolver software (NanoString Technology). The results showed that early-onset preeclampsia placentas displayed reduced expression of complement, and toll-like receptor (TLR) associated genes, specifically TLR1 and TLR4. Mast cells and M2 macrophages were also decreased in early-onset preeclampsia compared to healthy pl acentas. The findings were confirmed by an immunohistochemistry approach using 20 healthy, 19 early-onset preeclampsia, and 10 late-onset preeclampsia placentas. We conclude that the placental innate immune system is altered in early-onset preeclampsia compared to uncomplicated pregnancies. The absence of these alterations in late-onset preeclampsia placentas indicates dissimilar immunological profiles. The study revealed distinct pathophysiological processes in earlyonset and late-onset preeclampsia placentas and imply that a tailored treatment to each subtype is desirable.
2021-12-13 | GSE190639 | GEO
Project description:The series is composed of thirty hybridizations for analysis of differentially expressed genes in normal placenta tissues from patients with normal labor and placenta tissues from patients with severe preeclampsia. Patients tissues samples were obtained from (Vasilis. Total RNA extraction was performed by using the MagNa Pure Compact RNA Isolation Kit (Roche Applied Science). Keywords: Gene expression study, Disease state Twenty-six out of 50 normal placentas were randomly selected to match with 17 preeclamptic placentas, accounting for parity. Microarrays were performed applying a direct comparison design.
2010-05-26 | E-GEOD-10588 | biostudies-arrayexpress
Project description:Objectives: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with human dermal fibroblast (HDF) activation. Methods: We measured serum IL11 levels in healthy volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches. Results: In patients with SSc, serum IL11 levels are elevated as compared to healthy controls. Transforming growth factor beta (TGFβ) isoforms 1, 2 or 3 induced IL11 secretion from HDFs, which highly express IL11RA and the gp130 co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 consistently and robustly stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation. IL11 induced STAT phosphorylation to a lesser extent than ERK and only at high IL11 concentrations. IL11-stimulated ERK activation and fibrosis phenotypes were absent in skin fibroblasts from patients with homozygous loss-of-function mutation in IL11RA. Inhibition of IL11 signaling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacologic inhibition of ERK activity. Conclusions: These data reveal an important contribution of IL11-related ERK activity for TGFβ-stimulated fibrosis phenotypes in HDFs and suggest IL11 as a potential therapeutic target in SSc.
2021-02-22 | GSE162966 | GEO
Project description:Analysis of genome-wide gene expression in placentas from women with preterm severe preeclampsia, with or without HELLP syndrome, compared to gestational age-matched controls. The hypothesis tested in the present study was that placental transcriptomic changes in preeclampsia are considerably different from controls. The results provide important information on placental transcriptomic changes in preeclampsia.
2018-12-30 | GSE66273 | GEO
Project description:We perform placental microRNA expression profiling to identify potential microRNAs involved in the development and pathogenesis of preeclampsia. microRNA expression profiling for serum was quantified by qPCR and evaluated at 12, 16, and 20 gestational weeks and at the time of preeclampsia diagnosis. Two groups were evaluated using TaqMan Low Density Array plates: a control group with 18 normotensive pregnant women and a preeclampsia group with 16 patients who developed preeclampsia during the follow-up period. The placental microRNA profile was assayed at delivery (7 cases and 7 controls) using the Illumina GAIIx sequencing platform.
2015-06-03 | GSE69452 | GEO
Project description:Dysregulated RNA editing is well documented in several diseases such as cancer. The extent to which RNA editing might be involved in diseases originated in the placenta such as preeclampsia remains unknown, because RNA editing has rarely been studied in the placenta. Here, the RNA editome is systematically profiled on placentae from 9 patients with early-onset severe preeclampsia (EOSPE) and 32 normal controls, and a widespread RNA editing dysregulation in EOSPE has been identified. The mis-edited gene set is enriched with known preeclampsia-associated genes and differentially expressed genes in EOSPE. The “RNA editing events” at two microRNA binding sites in 3’-UTR of the LEP mRNA have been generated, which leads to increased expression level of LEP in trophoblast cells. Upregulation of LEP is also observed in the placentae of PE patients. These results suggest that widespread placental RNA editing may be involved in placental development and dysregulation of RNA editing in the placenta may contribute to the pathogenesis of preeclampsia.
2020-04-20 | GSE148241 | GEO
Project description:The series is composed of thirty hybridizations for analysis of differentially expressed genes in normal placenta tissues from patients with normal labor and placenta tissues from patients with severe preeclampsia. Patients tissues samples were obtained from (Vasilis. Total RNA extraction was performed by using the MagNa Pure Compact RNA Isolation Kit (Roche Applied Science). Keywords: Gene expression study, Disease state
2008-06-20 | GSE10588 | GEO
Project description:Placental Immune alterations in early-onset preeclampsia and late-onset preeclampsia
| PRJNA787896 | ENA