Inhibition of LTβR signalling activates WNT-induced regeneration in lung

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 Angelidis, Chiara Ciminieri, Rita Costa, Marlene Sophia Kohlhepp, Adrien Guillot, Gizem Günes, Aicha Jeridi, Maja C. Funk, Giorgi Beroshvili, Sandra Prokosch, Jenny Hetzer, Stijn E. Verleden, Hani Alsafadi, Michael Lindner, Gerald Burgstaller, Lore Becker, Martin Irmler, Michael Dudek, Jakob Janzen, Eric Goffin, Reinoud Gosens, Percy Knolle, Bernard Pirotte, Tobias Stoeger, Johannes Beckers, Darcy Wagner, Indrabahadur Singh, Fabian J. Theis, Martin Hrabé Angelis, Tracy O’Connor, Frank Tacke, Michael Boutros, Emmanuel Dejardin, Oliver Eickelberg, Herbert B. Schiller, Melanie Königshoff, Mathias Heikenwalder () and Ali Önder Yildirim ()
Additional contact information
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)
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
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)
Michael Lindner: 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
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
Darcy Wagner: Member of the German Center for Lung Research (DZL)
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
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
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)
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)

Nature, 2020, vol. 588, issue 7836, 151-156

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2882-8

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