IL-11 is a crucial determinant of cardiovascular fibrosis (mouse single cell)
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PROVIDER: PRJNA421910 | ENA |
REPOSITORIES: ENA
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Project description:Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging–genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signaling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
2017-12-11 | GSE107909 | GEO
Project description:Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
| S-EPMC5807082 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here we show that IL-11 is upregulated in the lung of IPF patients, associated with disease severity and is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive, ACTA2+ve, collagen secreting myofibroblasts, in an ERK-dependent fashion. In mice, fibroblast-specific transgenic expression or administration of Il-11 drives lung fibroblast-to-myofibroblast transformation and causes lung fibrosis. Il11ra1 deleted mice, whose lung fibroblasts are unresponsive to pro-fibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11 neutralising antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment both prevented and reversed lung fibrosis, which was accompanied by diminished Erk activation. These data prioritise IL-11 as a drug target for lung fibrosis and IPF.
2022-05-06 | GSE130983 | GEO
Project description:C/EBPα is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition
| PRJNA601109 | ENA
Project description:The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the CNS. We report that IL-11 is produced at highest frequency by myeloid cells among the PBMC cell subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes and IL-11R+ neutrophils in comparison to matched healthy controls (HCs). IL-11+ and GM-CSF+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single cell RNA sequencing (scRNAseq), revealed the highest number of differentially expressed genes (DEGs) in classical monocytes, including upregulated NFKB1, NLRP3 and IL1B. All CD4+ cell subsets had increased expression of S100A8/9 alarmin genes involved in NLRP3 inflammasome activation. In IL-11R+-sorted cells from the CSF, classical and intermediate monocytes significantly upregulated the expression of multiple NLRP3 inflammasome-related genes, including complement, IL18, and migratory genes (VEGFA/B) in comparison to blood-derived cells. Therapeutic targeting of this pathway with aIL-11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates and demyelination. aIL-11 mAb treatment decreased the numbers of NFkBp65+, NLRP3+ and IL-1b+ monocytes in the CNS of mice with EAE. The results suggest that IL-11/IL-11R signaling in monocytes represents a therapeutic target in RRMS.
2023-06-21 | GSE233917 | GEO
Project description:Orbital fibrosis is a hallmark of tissue remodeling in thyroid-associated ophthalmopathy (TAO). Previous studies have shown that interleukin (IL)-11 plays a pivotal profibrotic role in various inflammatory and autoimmune diseases. However, the expression pattern of IL-11 in patients with TAO and whether IL-11 is mechanistically linked with pathological fibrosis remains unknown. In this study, we investigated IL-11 levels in the serum and orbital connective tissue of patients with TAO, and evaluated the correlation of these levels with the patient’s clinical activity score. We also evaluated the expression pattern of IL-11Rα in orbital connective tissue. Furthermore, we elucidated the regulatory factors, profibrotic function, and downstream signaling pathways for IL-11 in TAO using in vitro studies. Serum and orbital connective tissues IL-11 levels were increased in patients with TAO, as compared with healthy controls. In addition, both levels were positively correlated with disease activity. Single-cell RNA sequencing of orbital connective tissue indicated that IL-11Rα was dominantly expressed in orbital fibroblasts (OFs). RNA sequencing of paired unstimulated and transforming growth factor (TGF)-β1-stimulated samples demonstrated that upregulation of IL-11 expression defined the dominant transcriptional response. IL-11 signaling was also confirmed to be downstream of TGF-β1 and IL-1β. Therefore, we deduced that IL-11 protein is secreted in an autocrine loop in TAO. We also indicated that IL-11 mediated the profibrotic phenotype switch by detecting the expression of myofibroblast differentiation markers, including α-smooth muscle actin and collagen type I α1, which could be abrogated by an anti-IL-11 neutralizing antibody. Furthermore, we revealed that extracellular regulated protein kinase may be a crucial factor in the pro-fibrotic, translationally specific signaling activity of IL-11. These data demonstrate that IL-11 plays a crucial role in orbital fibroblast phenotype switching and may be a potential therapeutic target candidate for the treatment of TAO.
2022-01-28 | GSE194322 | GEO
Project description:Orbital fibrosis is a hallmark of tissue remodeling in thyroid-associated ophthalmopathy (TAO). Previous studies have shown that interleukin (IL)-11 plays a pivotal profibrotic role in various inflammatory and autoimmune diseases. However, the expression pattern of IL-11 in patients with TAO and whether IL-11 is mechanistically linked with pathological fibrosis remains unknown. In this study, we investigated IL-11 levels in the serum and orbital connective tissue of patients with TAO, and evaluated the correlation of these levels with the patient’s clinical activity score. We also evaluated the expression pattern of IL-11Rα in orbital connective tissue. Furthermore, we elucidated the regulatory factors, profibrotic function, and downstream signaling pathways for IL-11 in TAO using in vitro studies. Serum and orbital connective tissues IL-11 levels were increased in patients with TAO, as compared with healthy controls. In addition, both levels were positively correlated with disease activity. Single-cell RNA sequencing of orbital connective tissue indicated that IL-11Rα was dominantly expressed in orbital fibroblasts (OFs). RNA sequencing of paired unstimulated and transforming growth factor (TGF)-β1-stimulated samples demonstrated that upregulation of IL-11 expression defined the dominant transcriptional response. IL-11 signaling was also confirmed to be downstream of TGF-β1 and IL-1β. Therefore, we deduced that IL-11 protein is secreted in an autocrine loop in TAO. We also indicated that IL-11 mediated the profibrotic phenotype switch by detecting the expression of myofibroblast differentiation markers, including α-smooth muscle actin and collagen type I α1, which could be abrogated by an anti-IL-11 neutralizing antibody. Furthermore, we revealed that extracellular regulated protein kinase may be a crucial factor in the pro-fibrotic, translationally specific signaling activity of IL-11. These data demonstrate that IL-11 plays a crucial role in orbital fibroblast phenotype switching and may be a potential therapeutic target candidate for the treatment of TAO.
2022-01-28 | GSE194323 | GEO
Project description:Background and aims: Here we investigate the role of IL-11 signalling in the pathogenesis of nonalcoholic steatohepatitis (NASH). Methods: HSCs or hepatocytes were stimulated with IL-11 and effects assessed using cellular and high content imaging, immunoblotting, ELISA and invasion assays. Genetic and pharmacological IL-11 gain- or loss-of-function experiments were performed in vitro and in vivo. IL-11 signaling was studied using ERK inhibitors. The effects of anti-IL-11 or anti-IL11RA therapy were assessed in three preclinical NASH models using methionine/choline deficient diets or a Western diet with liquid fructose. Phenotyping was performed using hydroxyproline assay, qPCR, RNA-seq, Western blotting, histology, CyTOF, lipid and metabolic biomarkers. Results: When stimulated with NASH factors HSCs secrete IL-11, which drives an autocrine, ERK-dependent signaling loop required for the HSC-to-myofibroblast transformation. IL-11 is upregulated in human and murine NASH, Il-11 injection causes liver damage, inflammation and fibrosis in mice and Il11ra1 deleted mice are protected from NASH in two preclinical models. Therapeutic antibodies against IL11RA or IL-11 consistently inhibit and reverse fibrosis and steatosis in three murine NASH models. Unexpectedly, IL-11 causes hepatocyte damage and promotes stromal-mediated inflammation and anti-IL-11 therapies reverse NASH-associated hepatotoxicity and hepatitis. Genetic or pharmacologic inhibition of IL-11 signaling in NASH is associated with lower serum triglyceride, cholesterol and glucose. Conclusion: We show an unappreciated and central role for IL-11 in liver pathobiology. Targeting IL-11 signalling with neutralizing antibodies reverses fibrosis, steatosis, hepatocyte death and inflammation across the spectrum of NASH. This novel therapeutic approach is associated with a favorable cardiometabolic profile.
2019-06-22 | GSE128940 | GEO
Project description:IL-11 is a therapeutic target in idiopathic pulmonary fibrosis
| PRJNA542170 | ENA
Project description:We performed micrarrays to analyse gene expression in spontaneously arising gastric tumors from gp130Y757F/F mutant mice (Tebbutt et al., 2002) following administration of recombinant human IL-6 or IL-11. The present study was designed to assess differences in gene expression in response to IL-6 and IL-11, two cytokines which both activate the shared gp130 receptor and downstream Stat3 signalling pathway. Since gastric tumorigenesis in gp130Y757F/F mice is strictly dependent on IL-11, but not IL-6 signalling (Ernst et al., 2008) the study aimed to identify IL-6 and IL-11 specific target genes which may account for the IL-11 dependent tumor development.
2013-08-10 | GSE43800 | GEO