دورية أكاديمية
أعرض في EDS

c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.

التفاصيل البيبلوغرافية
العنوان: c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.
المؤلفون: Leslie J; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. jack.leslie@newcastle.ac.uk., Macia MG; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Luli S; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Worrell JC; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Reilly WJ; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Paish HL; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Knox A; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Barksby BS; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Gee LM; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Zaki MYW; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.; Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt., Collins AL; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Burgoyne RA; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Cameron R; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Bragg C; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Xu X; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Chung GW; Newcells Biotech, The Biosphere, Newcastle Helix, Newcastle upon Tyne, UK., Brown CDA; Newcells Biotech, The Biosphere, Newcastle Helix, Newcastle upon Tyne, UK., Blanchard AD; Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, UK., Nanthakumar CB; Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, UK., Karsdal M; Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark., Robinson SM; Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Manas DM; Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Sen G; Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., French J; Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., White SA; Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Murphy S; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Trost M; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Zakrzewski JL; Center for Discovery and Innovation and John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA., Klein U; Division of Haematology & Immunology, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK., Schwabe RF; Department of Medicine, Columbia University, New York, NY, USA., Mederacke I; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany., Nixon C; Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK., Bird T; Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.; MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Teuwen LA; Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium., Schoonjans L; Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium., Carmeliet P; Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium., Mann J; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.; Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK., Fisher AJ; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.; Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Sheerin NS; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Borthwick LA; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.; Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK., Mann DA; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.; Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK., Oakley F; Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. fiona.oakley@newcastle.ac.uk.; Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK. fiona.oakley@newcastle.ac.uk.
المصدر: Nature metabolism [Nat Metab] 2020 Nov; Vol. 2 (11), pp. 1350-1367. Date of Electronic Publication: 2020 Nov 09.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Springer Nature Country of Publication: Germany NLM ID: 101736592 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2522-5812 (Electronic) Linking ISSN: 25225812 NLM ISO Abbreviation: Nat Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Berlin : Springer Nature, [2019]-
مواضيع طبية MeSH: Epithelium/*pathology , Liver Cirrhosis/*genetics , Liver Cirrhosis/*pathology , Macrophages/*pathology , Proto-Oncogene Proteins c-rel/*genetics, Animals ; Cell Polarity/genetics ; Gene Targeting ; Hepatocytes/pathology ; Hydroxyproline/metabolism ; Liver Cirrhosis/prevention & control ; Liver Regeneration/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitosis/genetics ; Paracrine Communication/genetics ; Phosphofructokinase-2/genetics ; Proto-Oncogene Proteins c-rel/antagonists & inhibitors ; Proto-Oncogene Proteins c-rel/metabolism
مستخلص: Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-β1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in Rel ΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.
التعليقات: Erratum in: Nat Metab. 2021 Jan;3(1):118-119. (PMID: 33303984)
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معلومات مُعتمدة: MR/K001949/1 United Kingdom MRC_ Medical Research Council; G0900535 United Kingdom MRC_ Medical Research Council; 26813 United Kingdom CRUK_ Cancer Research UK; A26813 United Kingdom CRUK_ Cancer Research UK; MR/R023026/1 United Kingdom MRC_ Medical Research Council; MR/L016354/1 United Kingdom MRC_ Medical Research Council; A23390 United Kingdom CRUK_ Cancer Research UK; A171196 United Kingdom CRUK_ Cancer Research UK; MR/K0019494/1 United Kingdom MRC_ Medical Research Council; WT107492Z United Kingdom WT_ Wellcome Trust; G0700890 United Kingdom MRC_ Medical Research Council; 23390 United Kingdom CRUK_ Cancer Research UK; NC/K000748/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; United Kingdom WT_ Wellcome Trust; MC_PC_14101 United Kingdom MRC_ Medical Research Council; L016354 United Kingdom MRC_ Medical Research Council; 20812 United Kingdom VAC_ Versus Arthritis; G0401643 United Kingdom MRC_ Medical Research Council; 087961 United Kingdom WT_ Wellcome Trust
المشرفين على المادة: 0 (Proto-Oncogene Proteins c-rel)
0 (REL protein, human)
EC 2.7.1.105 (PFKFB3 protein, mouse)
EC 2.7.1.105 (Phosphofructokinase-2)
RMB44WO89X (Hydroxyproline)
تواريخ الأحداث: Date Created: 20201110 Date Completed: 20201231 Latest Revision: 20240212
رمز التحديث: 20240212
مُعرف محوري في PubMed: PMC7116435
DOI: 10.1038/s42255-020-00306-2
PMID: 33168981
قاعدة البيانات: MEDLINE
الوصف
تدمد:2522-5812
DOI:10.1038/s42255-020-00306-2