Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Next-generation sequencing reveals IL11 drives preeclampsia by disrupting trophoblast differentiation and activating the placental inflammasome

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE193685 | GEO | 2023/05/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [human]

Project description:Cardiac fibrosis is the final common pathology in heart disease. Here we establish an integrated imaging-genomic discovery platform using primary human heart fibroblasts to identify new drug targets for cardiac fibrosis. Genome wide analyses identify IL11, a secreted cytokine amenable to therapeutic inhibition, as the leading pro-fibrotic candidate. We demonstrate an autocrine loop of IL11 activity that is critical for fibrosis and acts as a nexus of signalling convergence for multiple pro-fibrotic stimuli. IL11 signals in cis and trans via the ERK cascade to activate a programme of fibrosis primarily at the level of protein translation. Injection of IL11 to mice causes fibrosis of the heart, kidney, lung, skin and liver whereas genetic ablation of the IL11 receptor prevented fibrosis across tissues. These data define a new non-canonical fibrogenic pathway and prioritise IL11 as a novel therapeutic target for fibrosis of the heart and other organs

2017-11-22 | GSE96975 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [mouse]

2017-11-22 | GSE96991 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [168 human cardiac fibroblasts]

2017-11-22 | GSE97358 | GEO

Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction

Project description:Background: Cardiac fibrosis is a common pathological process in heart disease and represents a therapeutic target. TGFβ is the canonical driver of cardiac fibrosis and was recently shown to be dependent on IL11 for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and also anti-inflammatory in the mouse heart. Objectives: In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. Methods: We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing and in vivo imaging we analysed the effects of IL11 on myocardial fibrosis, inflammation and cardiac function and challenge previous reports suggesting cardioprotective potential of IL11. Results: TGFβ stimulation of cardiomyocytes caused Il11 upregulation. As compared to wild-type controls, Il11 expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors and increased inflammatory cells. IL11 expression also activated a programme of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Conclusion: Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.

2023-08-21 | GSE236854 | GEO

IL11 is elevated in systemic sclerosis and IL11-dependent ERK signaling is needed for the profibrotic activity of TGFβ in dermal fibroblasts

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

Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction

Project description:Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction

| PRJNA992522 | ENA

Next-generation sequencing reveals IL11 drives preeclampsia by disrupting trophoblast differentiation and activating the placental inflammasome

Project description:Next-generation sequencing reveals IL11 drives preeclampsia by disrupting trophoblast differentiation and activating the placental inflammasome

| PRJNA797243 | ENA

Comparison of gene expression profiles in naïve WT and Asc-null bone marrow derived dendritic cells

Project description:The adaptor protein ASC contributes to innate immunity through the assembly of caspase-1-activating inflammasome complexes. We demonstrate that ASC plays an inflammasome-independent cell-intrinsic role in adaptive immune cells. Asc-/- mice displayed defective antigen presentation by dendritic cells and lymphocyte migration due to impaired Rac-mediated actin polymerization. Genome-wide analysis showed that ASC, but not Nlrp3 or caspase-1, controls mRNA stability and expression of DOCK2, a guanine nucleotide exchange factor that mediates Rac-dependent signaling in immune cells. DOCK2-deficient dendritic cells showed similar defective antigen uptake as Asc-/- cells. Ectopic expression of DOCK2 in ASC-deficient cells restored Rac-mediated actin polymerization, antigen uptake and chemotaxis. Thus, ASC shapes adaptive immunity independently of inflammasomes by modulating DOCK2-dependent Rac activation and F-actin polymerization in dendritic cells and lymphocytes. Three replicates of naïve WT and three replicates of Asc-/- bone marrow derived dendritic cells were analyzed on the Affymetrix HT MG-430 PM plate array.

2012-07-08 | E-GEOD-30769 | biostudies-arrayexpress

The difference of placental fibroblast between normal pregnancy and preeclampsia

Project description:Fibrosis are known as one of the characteristic pathological findings of placenta in preeclampsia (PE). The mechanism underlying tissue injury when placental stroma is exposed to hypoxia and inflammatory stimulation is unclear. We focused on the relationship between pathogenesis of PE and placental fibrosis, and investigated the changes of fibrosis related factors (FRFs) in placental stroma. The mRNA levels of fibrosis related factors in PE were higher than those in normal pregnancy (NP). Those under hypoxia and by TGF-β stimulation were more prominent in PE compared with NP. The contraction rate of PE had significantly higher than that of NP. The significant elevation of plasma level of TGF-β in PE was indicated compared with those in NP.

2017-05-18 | GSE99007 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis

Project description:Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis

| PRJNA380739 | ENA