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Inhibition of LTβR signalling activates WNT-induced regeneration in lung

Conlon, Thomas M (author)
Helmholtz Zentrum München
John-Schuster, Gerrit (author)
Heide, Danijela (author)
German Cancer Research Centre
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Pfister, Dominik (author)
German Cancer Research Centre
Lehmann, Mareike (author)
Helmholtz Zentrum München
Hu, Yan (author)
University of Northern Colorado
Ertüz, Zeynep (author)
Lopez, Martin A (author)
University of Liège Hospital
Ansari, Meshal (author)
Strunz, Maximilian (author)
Mayr, Christoph (author)
Ciminieri, Chiara (author)
University of Northern Colorado
Costa, Rita (author)
Kohlhepp, Marlene Sophia (author)
Charité - University Medicine Berlin
Guillot, Adrien (author)
Charité - University Medicine Berlin
Günes, Gizem (author)
Jeridi, Aicha (author)
Funk, Maja C (author)
German Cancer Research Centre
Beroshvili, Giorgi (author)
Prokosch, Sandra (author)
German Cancer Research Centre
Hetzer, Jenny (author)
German Cancer Research Centre
Verleden, Stijn E (author)
Alsafadi, Hani (author)
Lund University,Lunds universitet,Lungbioengineering och regeneration,Forskargrupper vid Lunds universitet,Lung Bioengineering and Regeneration,Lund University Research Groups,German Center for Lung Research (DZL),Helmholtz Zentrum München
Lindner, Michael (author)
German Center for Lung Research (DZL)
Burgstaller, Gerald (author)
Becker, Lore (author)
University of Warsaw
Irmler, Martin (author)
University of Warsaw
Dudek, Michael (author)
Technical University of Munich
Janzen, Jakob (author)
German Cancer Research Centre
Goffin, Eric (author)
University of Liège Hospital
Gosens, Reinoud (author)
Hanze University of Applied Sciences
Knolle, Percy (author)
Technical University of Munich
Pirotte, Bernard (author)
University of Liège Hospital
Stoeger, Tobias (author)
Beckers, Johannes (author)
University of Warsaw
Wagner, Darcy (author)
Lund University,Lunds universitet,Lungbioengineering och regeneration,Forskargrupper vid Lunds universitet,Lung Bioengineering and Regeneration,Lund University Research Groups,Helmholtz Zentrum München,German Center for Lung Research (DZL)
Singh, Indrabahadur (author)
German Cancer Research Centre
Theis, Fabian J (author)
Helmholtz Zentrum München
de Angelis, Martin Hrabé (author)
University of Warsaw
O'Connor, Tracy (author)
German Cancer Research Centre
Tacke, Frank (author)
Charité - University Medicine Berlin
Boutros, Michael (author)
German Cancer Research Centre
Dejardin, Emmanuel (author)
University of Liège Hospital
Eickelberg, Oliver (author)
University of Northern Colorado
Schiller, Herbert B (author)
Königshoff, Melanie (author)
Heikenwalder, Mathias (author)
German Cancer Research Centre
Yildirim, Ali Önder (author)
Helmholtz Zentrum München
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 (creator_code:org_t)
2020-11-04
2020
English 6 s.
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 588:7836, s. 151-156
Related links:
http://dx.doi.org/10...
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https://www.ncbi.nlm...
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Lungmedicin och allergi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Respiratory Medicine and Allergy (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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