Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα-TRAF3-TAK1-MAPK axis
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ABSTRACT:
PROVIDER: PRJNA1156638 | ENA |
REPOSITORIES: ENA
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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.
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Project description:Specific deletion of the tumor suppressor gene TRAF3 from B lymphocytes (B-TRAF3-/-) in mice leads to prolonged survival of mature B cells and expanded B cell compartment in secondary lymphoid organs. To understand the metabolic basis of the prolonged survival of TRAF3-/- B cells, we performed LC-MS-based metabolome and lipidome screening with resting splenic B cells of young adult B-TRAF3-/- and littermate control (LMC) mice. Our metabolome screening data showed that phosphocholine (P-Cho) and phosphoethanolamine, two small metabolites and precursors of phospholipids, were significantly increased in TRAF3-/- B cells. Consistently, our lipidome screening revealed markedly elevated levels of multiple species of phosphatidylcholine (PC) and phosphatidylethanolamine in TRAF3-/- B cells. Interestingly, our transcriptome profiling identified Chka, the rate-limiting enzyme of choline metabolism, as a significantly up-regulated gene in TRAF3-/- B cells. To investigate the functional importance of elevated choline metabolism, we examined the effects of two Chka inhibitors, MN58B and RSM932A. We found that both MN58B and RSM932A potently induced cell apoptosis in TRAF3-/- mouse B lymphoma and human multiple myeloma cell lines in vitro. Furthermore, in vivo administration of MN58B and RSM932A partially decreased the spleen size and B cell compartment in B-TRAF3-/- mice. Together, our results indicate that TRAF3 specifically re-engineers the P-Cho-PC-PE metabolic pathways to regulate mature B cell survival. Our findings also suggest that the P-Cho-PC-PE metabolic pathways have diagnostic and therapeutic value for B cell malignancies with TRAF3 deletion or relevant mutations.
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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.
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