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Inhibition of LTβR signalling activates WNT-induced regeneration in lung

Conlon, Thomas M ; John-Schuster, Gerrit ; Heide, Danijela ; Pfister, Dominik ; Lehmann, Mareike ; Hu, Yan ; Ertüz, Zeynep ; Lopez, Martin A ; Ansari, Meshal and Strunz, Maximilian , et al. (2020) In Nature 588(7836). p.151-156
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
588
issue
7836
pages
6 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:33149305
  • scopus:85094974819
ISSN
0028-0836
DOI
10.1038/s41586-020-2882-8
language
English
LU publication?
yes
id
5ad60433-79f0-4b25-8bb8-e356200ba240
date added to LUP
2020-11-09 09:55:26
date last changed
2024-06-14 02:06:25
@article{5ad60433-79f0-4b25-8bb8-e356200ba240,
  abstract     = {{<p>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.</p>}},
  author       = {{Conlon, Thomas M and John-Schuster, Gerrit and Heide, Danijela and Pfister, Dominik and Lehmann, Mareike and Hu, Yan and Ertüz, Zeynep and Lopez, Martin A and Ansari, Meshal and Strunz, Maximilian and Mayr, Christoph and Ciminieri, Chiara and Costa, Rita and Kohlhepp, Marlene Sophia and Guillot, Adrien and Günes, Gizem and Jeridi, Aicha and Funk, Maja C and Beroshvili, Giorgi and Prokosch, Sandra and Hetzer, Jenny and Verleden, Stijn E and Alsafadi, Hani and Lindner, Michael and Burgstaller, Gerald and Becker, Lore and Irmler, Martin and Dudek, Michael and Janzen, Jakob and Goffin, Eric and Gosens, Reinoud and Knolle, Percy and Pirotte, Bernard and Stoeger, Tobias and Beckers, Johannes and Wagner, Darcy and Singh, Indrabahadur and Theis, Fabian J and de Angelis, Martin Hrabé and O'Connor, Tracy and Tacke, Frank and Boutros, Michael and Dejardin, Emmanuel and Eickelberg, Oliver and Schiller, Herbert B and Königshoff, Melanie and Heikenwalder, Mathias and Yildirim, Ali Önder}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{7836}},
  pages        = {{151--156}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Inhibition of LTβR signalling activates WNT-induced regeneration in lung}},
  url          = {{http://dx.doi.org/10.1038/s41586-020-2882-8}},
  doi          = {{10.1038/s41586-020-2882-8}},
  volume       = {{588}},
  year         = {{2020}},
}