Author
Listed:
- Thomas M. Conlon
(Member of the German Center for Lung Research (DZL))
- Gerrit John-Schuster
(Member of the German Center for Lung Research (DZL))
- Danijela Heide
(German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer)
- Dominik Pfister
(German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer)
- Mareike Lehmann
(Member of the German Center for Lung Research (DZL))
- Yan Hu
(University of Colorado)
- Zeynep Ertüz
(Member of the German Center for Lung Research (DZL))
- Martin A. Lopez
(University of Liège)
- Meshal Ansari
(Member of the German Center for Lung Research (DZL)
Institute of Computional Biology (ICB), Helmholtz Zentrum München)
- Maximilian Strunz
(Member of the German Center for Lung Research (DZL))
- Christoph Mayr
(Member of the German Center for Lung Research (DZL))
- Ilias Angelidis
(Member of the German Center for Lung Research (DZL))
- Chiara Ciminieri
(University of Colorado
University of Groningen)
- Rita Costa
(Member of the German Center for Lung Research (DZL))
- Marlene Sophia Kohlhepp
(Charité University Medicine Berlin)
- Adrien Guillot
(Charité University Medicine Berlin)
- Gizem Günes
(Member of the German Center for Lung Research (DZL))
- Aicha Jeridi
(Member of the German Center for Lung Research (DZL))
- Maja C. Funk
(German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics)
- Giorgi Beroshvili
(Member of the German Center for Lung Research (DZL))
- Sandra Prokosch
(German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer)
- Jenny Hetzer
(German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer)
- Stijn E. Verleden
(Division of Pneumology)
- Hani Alsafadi
(Member of the German Center for Lung Research (DZL)
Lund University)
- Michael Lindner
(Member of the German Center for Lung Research (DZL)
Member of the German Center for Lung Research (DZL))
- Gerald Burgstaller
(Member of the German Center for Lung Research (DZL))
- Lore Becker
(German Mouse Clinic, Helmholtz Zentrum München)
- Martin Irmler
(German Mouse Clinic, Helmholtz Zentrum München)
- Michael Dudek
(Technical University of Munich)
- Jakob Janzen
(German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer
German Cancer Research Center (DKFZ))
- Eric Goffin
(University of Liège)
- Reinoud Gosens
(University of Groningen)
- Percy Knolle
(Technical University of Munich)
- Bernard Pirotte
(University of Liège)
- Tobias Stoeger
(Member of the German Center for Lung Research (DZL))
- Johannes Beckers
(German Mouse Clinic, Helmholtz Zentrum München
Technische Universität München
German Center for Diabetes Research (DZD))
- Darcy Wagner
(Member of the German Center for Lung Research (DZL)
Lund University)
- Indrabahadur Singh
(German Cancer Research Center (DKFZ))
- Fabian J. Theis
(Institute of Computional Biology (ICB), Helmholtz Zentrum München)
- Martin Hrabé Angelis
(German Mouse Clinic, Helmholtz Zentrum München
University of Liège
Technische Universität München)
- Tracy O’Connor
(German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer)
- Frank Tacke
(Charité University Medicine Berlin)
- Michael Boutros
(German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics
Heidelberg University)
- Emmanuel Dejardin
(University of Liège)
- Oliver Eickelberg
(University of Colorado)
- Herbert B. Schiller
(Member of the German Center for Lung Research (DZL))
- Melanie Königshoff
(Member of the German Center for Lung Research (DZL)
University of Colorado)
- Mathias Heikenwalder
(German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer)
- Ali Önder Yildirim
(Member of the German Center for Lung Research (DZL))
Abstract
Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures1,2, which are associated with severe chronic inflammatory diseases that span several organ systems3–6. How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR 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 LTβR 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 LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.
Suggested Citation
Thomas M. Conlon & Gerrit John-Schuster & Danijela Heide & Dominik Pfister & Mareike Lehmann & Yan Hu & Zeynep Ertüz & Martin A. Lopez & Meshal Ansari & Maximilian Strunz & Christoph Mayr & Ilias Ange, 2020.
"Inhibition of LTβR signalling activates WNT-induced regeneration in lung,"
Nature, Nature, vol. 588(7836), pages 151-156, December.
Handle:
RePEc:nat:nature:v:588:y:2020:i:7836:d:10.1038_s41586-020-2882-8
DOI: 10.1038/s41586-020-2882-8
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