Blockade of the Protease ADAM17 Ameliorates Experimental Pancreatitis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA886653 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21786372.fastq.gz | Fastqsanger.gz | |||
| SRR21786373.fastq.gz | Fastqsanger.gz | |||
| SRR21786374.fastq.gz | Fastqsanger.gz | |||
| SRR21786375.fastq.gz | Fastqsanger.gz | |||
| SRR21786376.fastq.gz | Fastqsanger.gz |
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Project description:Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalisation, including death. Despite the global health burden of pancreatitis, currently there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumour necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signalling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17ex/ex mice – which are homozygous for the hypomorphic Adam17ex allele resulting in marked reduction in ADAM17 expression – and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-week) and chronic (20-weeks) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was upregulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (Adam17ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor; A17pro) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signalling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, upregulation of the ADAM17/IL-6 trans-signalling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.
2022-10-06 | GSE214666 | GEO
Project description:Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumor necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signaling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17ex/ex mice-which are homozygous for the hypomorphic Adam17ex allele resulting in marked reduction in ADAM17 expression-and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-wk) and chronic (20-wk) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was up-regulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (Adam17ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor [A17pro]) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signaling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, up-regulation of the ADAM17/IL-6 trans-signaling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.
| S-EPMC9586293 | biostudies-literature
Project description:Adam17, a shedding protease, is strongly upregtulated during inflammation and cancer. Here we investigate the genome wide effects of Adam17 knock out on the transcriptome. Mouse tissue samples from n=3 wildtype colon, n=3 Adam17 knockout colon, n=3 wildtype skin and n=3 Adam17 knockout skin were used in the study.
2010-07-08 | E-GEOD-21691 | biostudies-arrayexpress
Project description:Adam17, a shedding protease, is strongly upregtulated during inflammation and cancer. Here we investigate the genome wide effects of Adam17 knock out on the transcriptome.
2010-06-18 | GSE21691 | GEO
Project description:Disintegrin and metalloproteinases ADAM10 and ADAM17 can release the extracellular region of a variety of membrane-bound proteins including cytokines, adhesion molecules, growth factors and receptors, important for many biological functions (ectodomain shedding).. So far, substrate identification for ADAM10 and ADAM17 focused exclusively on their membrane-anchored forms and their function as sheddases. With ADAM8 we now describe the first protease capable of releasing the ADAM17 ectodomain. Based on these findings, we investigated whether the soluble ectodomains of ADAM10 and ADAM17 still exhibit shedding activity and to determine their soluble protein substrate pool . To address this, a mass spectrometry-based N-terminomics approach (TAILS) was used to identify potential targets of soluble ADAM10 and ADAM17 (sADAM10/17) within the secretome of the murine cardiomyocyte cell line HL-1. We identified almost 140 protein cleavage events in total and 45 common substrates for both sADAM10 and sADAM17. Further in-vitro studies confirmed fibronectin, cystatin C, sN-cadherin, PCPE-1 as well as sAPP as direct substrates of soluble ADAM10 and/or ADAM17. Overall, we present the first degradome study for sADAM10 and sADAM17, thereby introducing a new regulation mode of the proteolytic activity of these essential proteases within the protease web.
2019-06-24 | PXD013718 | Pride
Project description:This study investigates the role of ADAM17 (a disintegrin and metalloproteinase 17) in skin homeostasis. Here, we show that mice lacking ADAM17 in keratinocytes have a normal epidermal barrier and skin architecture at birth, but develop pronounced defects in epidermal barrier integrity soon after birth and chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 days after birth, followed by transepidermal water loss and inflammatory immune cell infiltration. Our results identify a previously unappreciated critical role of the ADAM17/EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier. The genome-wide effects of ADAM17 deficiency were analyzed using Agilent Whole Mouse Genome microarrays. Conditional keratinocyte-specific ADAM17 knockout mice were generated by crossing Adam17flox/flox mice with keratin-14-Cre (Krt14-Cre) transgenic mice. Adam17flox/+Krt14-Cre mice were mated with Adam17flox/flox mice to generate pups of Adam17flox/flox Krt14-Cre positive (cKO) and Krt14-Cre negative (wild-type) control littermates. The genetic background was a mix of 129Sv and C57BL/6. As material, back skin tissue biopsies (postnatal day 10) from n = 2 wild-type skin and n = 2 ADAM17 epidermal KO skin (matched WT-cKO pairs from two different litters) were used in this study.
2012-06-20 | E-GEOD-38830 | biostudies-arrayexpress
Project description:The apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas tissue homeostasis are poorly understood. Here, we evaluate the role of Par3 in acinar pancreas injury and homeostasis. While Par3 loss in the mouse pancreas disrupts tight junctions, Par3 loss is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss also exacerbates pancreatitis-induced acinar cell loss, resulting in pronounced pancreatic lipomatosis and failure to regenerate. Moreover, Par3 loss in mice harboring mutant Kras causes extensive pancreatic intraepithelial neoplastic (PanIN) lesions and large pancreatic cysts. We also show that Par3 loss restricts injury-induced primary ciliogenesis. Significantly, targeting BET proteins enhances primary ciliogenesis during pancreatitis-induced injury and, in mice with Par3 loss, limits pancreatitis-induced acinar loss and facilitates acinar cell regeneration. Combined, this study demonstrates how Par3 restrains pancreatitis- and Kras-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate pancreas tissue regeneration.
2024-08-05 | GSE243623 | GEO
Project description:Ectodomain shedding, which is the proteolytic release of transmembrane proteins from the cell surface, is crucial for cell-to-cell communication and other biological processes. The metalloproteinase ADAM17 mediates ectodomain shedding of over 50 transmembrane proteins ranging from cytokines and growth factors, such as TNF and EGFR ligands, to signaling receptors and adhesion molecules. Yet, the ADAM17 sheddome is only partly defined and biological functions of the protease have not been fully characterized. Some ADAM17 substrates (e.g. HB-EGF) are known to bind to heparan sulfate proteoglycans (HSPG), and we hypothesised that such substrates would be under-represented in traditional secretome analyses, due to their binding to cell surface or pericellular HSPGs. Thus, to identify novel HSPG-binding ADAM17 substrates, we developed a proteomic workflow that involves addition of heparin to solubilize HSPG-binding proteins from the cell layer, thereby allowing their mass spectrometry detection by heparin-secretome (HEP-SEC) analysis. Applying this methodology to murine embryonic fibroblasts stimulated with an ADAM17 activator enabled us to identify 47 transmembrane proteins that were shed in response to ADAM17 activation. This included known HSPG-binding ADAM17 substrates (i.e. HB-EGF, CX3CL1) and 14 novel HSPG-binding putative ADAM17 substrates.
2024-10-15 | PXD055223 | Pride
Project description:Autoimmune pancreatitis (AIP) is a recently identified disease of the pancreas with unknown etiology and antigens. The aim of this study was to determine new target antigens and differentially regulated genes and proteins by means of transcriptomics and proteomics and to validate them in patients with autoimmune pancreatitis. Here we report a distinct downregulation at the RNA and protein level of pancreatic proteases (anionic trypsinogen, cationic trypsinogen, mesotrypsinogen, elastase IIIB) and pancreatic stone protein in autoimmune pancreatitis in comparison to alcohol-induced chronic pancreatitis.
2008-12-31 | E-MEXP-804 | biostudies-arrayexpress
Project description:Human cytomegalovirus (HCMV) is a major human pathogen whose life-long persistence is enabled by its remarkable capacity to systematically subvert host immune defences. In exploring the finding that HCMV infection upregulates tumor necrosis factor receptor 2 (TNFR2), a ligand for the proinflammatory anti-viral cytokine TNFa, we discovered the underlying mechanism was due to targeting of the protease, A Disintegrin And Metalloproteinase 17 (ADAM17). ADAM17 is the prototype ‘sheddase, a family of proteases that cleaves other membrane-bound proteins to release biologically active ectodomains into the supernatant. HCMV impaired ADAM17 surface expression through the action of two virally-encoded proteins in its UL/b’ region, UL148 and UL148D. Proteomic plasma membrane profiling of cells infected with a HCMV double deletion mutant for UL148 and UL148D with restored ADAM17 expression, combined with ADAM17 functional blockade, showed that HCMV stabilized the surface expression of 114 proteins (p<0.05) in an ADAM17-dependent fashion. These included known substrates of ADAM17 with established immunological functions such as TNFR2 and Jagged1, but also numerous novel host and viral targets, such as Nectin1, UL8 and UL144. Regulation of TNFa-induced cytokine responses and NK inhibition during HCMV infection were dependent on this impairment of ADAM17. We therefore identify a viral immunoregulatory mechanism in which targeting a single sheddase enables broad regulation of multiple critical surface receptors, revealing a paradigm for viral-encoded immunomodulation.
2023-10-11 | PXD044082 | Pride