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

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

PROVIDER: PRJNA683969 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13234405_1.fastq.gz	Fastqsanger.gz
	SRR13234405_2.fastq.gz	Fastqsanger.gz
	SRR13234406_1.fastq.gz	Fastqsanger.gz
	SRR13234406_2.fastq.gz	Fastqsanger.gz
	SRR13234407_1.fastq.gz	Fastqsanger.gz

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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: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 signalling underlies TGFβ-mediated activation of dermal fibroblasts.

Project description:ObjectivesInterleukin 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 activation of human dermal fibroblasts (HDFs) from patients with SSc or controls.MethodsWe measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping.ResultsIn patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling 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 pharmacological inhibition of ERK.ConclusionsThese data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFβ stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc.

| S-EPMC8645270 | biostudies-literature

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

Integrin beta-1 (Itgb1) in profibrotic myofibroblasts

Project description:Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes profibrotic features. This microarray study was performed to clarify the role of integrin beta-1 (Itgb1) in profibrotic myofibroblasts.

2016-08-18 | E-MTAB-4810 | biostudies-arrayexpress

Cenicriviroc reduces liver fibrosis by restoring the immune cell landscape via inactivating STAT1/NF&B/ERK signaling pathways [treatment_scRNA-seq]

Project description:This study depicts a novel mechanism by which CVC alleviates liver fibrosis by restoring the immune cell landscape. CVC can inhibit profibrotic gene transcription via inactivating the CCR2-STAT1/NF&B/ERK signaling pathways.

2023-08-31 | GSE218496 | GEO

Cenicriviroc reduces liver fibrosis by restoring the immune cell landscape via inactivating STAT1/NF&B/ERK signaling pathways [prevention_RNA-seq]

2023-08-31 | GSE218497 | GEO

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

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

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