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Inhibition of LTβR signalling activates WNT-induced regeneration in lung

التفاصيل البيبلوغرافية
العنوان: Inhibition of LTβR signalling activates WNT-induced regeneration in lung
المؤلفون: Zeynep Ertüz, Giorgi Beroshvili, Dominik Pfister, Adrien Guillot, Oliver Eickelberg, Mathias Heikenwalder, Eric Goffin, Reinoud Gosens, Gerald Burgstaller, Danijela Heide, Maximilian Strunz, Fabian J. Theis, Mareike Lehmann, Martin A. Lopez, Michael Boutros, Aicha Jeridi, Darcy E. Wagner, Yan Hu, Marlene Kohlhepp, Tracy O'Connor, Lore Becker, Frank Tacke, Thomas M. Conlon, Meshal Ansari, Indrabahadur Singh, Christoph Mayr, Martin Hrabé de Angelis, Tobias Stoeger, Emmanuel Dejardin, Hani N. Alsafadi, Melanie Königshoff, Sandra Prokosch, Chiara Ciminieri, Michael Dudek, Bernard Pirotte, Herbert B. Schiller, Johannes Beckers, Maja C. Funk, Percy A. Knolle, Martin Irmler, Stijn E. Verleden, Michael Lindner, Gizem Gunes, Rita Costa, Jenny Hetzer, Gerrit John-Schuster, Jakob Janzen, Ali Önder Yildirim
المساهمون: Groningen Research Institute for Asthma and COPD (GRIAC), Molecular Pharmacology, Nanomedicine & Drug Targeting
المصدر: Nature, 588(7836), 151-156. Nature Publishing Group
Nature
سنة النشر: 2019
مصطلحات موضوعية: 0301 basic medicine, Aging, Apoptosis, Adaptive Immunity, Article, 03 medical and health sciences, Mice, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Fibrosis, Lymphotoxin beta Receptor, Smoke, medicine, Animals, Humans, Regeneration, Progenitor cell, Lung, beta Catenin, Emphysema, Multidisciplinary, Innate immune system, business.industry, Regeneration (biology), Stem Cells, Wnt signaling pathway, NF-kappa B, Acquired immune system, medicine.disease, Epithelium, Immunity, Innate, 3. Good health, Mice, Inbred C57BL, Wnt Proteins, 030104 developmental biology, Lymphotoxin, medicine.anatomical_structure, 030228 respiratory system, Alveolar Epithelial Cells, Cancer research, Female, business, Engineering sciences. Technology, Signal Transduction
الوصف: Blockade of lymphotoxin beta-receptor (LT beta R) signalling restores WNT signalling and epithelial repair in a model of chronic obstructive pulmonary disease. Lymphotoxin beta-receptor (LT beta R) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures(1,2), which are associated with severe chronic inflammatory diseases that span several organ systems(3-6). How LT beta R signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LT beta R blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LT beta R ligands in adaptive and innate immune cells, enhanced non-canonical NF-kappa B signalling, and enriched LT beta R target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LT beta R signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LT beta R signalling dampened epithelial non-canonical activation of NF-kappa B, reduced TGF beta signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/beta-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LT beta R signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures(1) and inhibition of apoptosis with tissue-regenerative strategies.
وصف الملف: application/pdf
تدمد: 1476-4687
0028-0836
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5772fcac548c1dcc51d1a568d335b290
https://pubmed.ncbi.nlm.nih.gov/33353984
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....5772fcac548c1dcc51d1a568d335b290
قاعدة البيانات: OpenAIRE
الوصف
تدمد:14764687
00280836