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Conlon, T.M. ; John-Schuster, G. ; Heide, D.* ; Pfister, D.* ; Lehmann, M. ; Hu, Y.* ; Ertüz, Z. ; López, M.A.* ; Ansari, M. ; Strunz, M. ; Mayr, C. ; Ciminieri, C.* ; Costa, R. ; Kohlhepp, M.S.* ; Guillot, A.* ; Güneş, G. ; Jeridi, A. ; Funk, M.C.* ; Beroshvili, G. ; Prokosch, S.* ; Hetzer, J.* ; Verleden, S.E.* ; Alsafadi, H.N. ; Lindner, M. ; Burgstaller, G. ; Becker, L. ; Irmler, M. ; Dudek, M.* ; Janzen, J.* ; Goffin, E.* ; Gosens, R.* ; Knolle, P.* ; Pirotte, B.* ; Stöger, T. ; Beckers, J. ; Wagner, D.E. ; Singh, I.* ; Theis, F.J. ; Hrabě de Angelis, M. ; O’Connor, T.* ; Tacke, F.* ; Boutros, M.* ; Dejardin, E.* ; Eickelberg, O.* ; Schiller, H. B. ; Königshoff, M. ; Heikenwalder, M.* ; Yildirim, A.Ö.

Inhibition of LTβR signalling activates WNT-induced regeneration in lung.

Nature, accepted (2020)
Publ. Version/Full Text DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Gene-expression; Lymphotoxin; Cells; Reveals; Pathway; Platform; Cancer; Repair
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Publisher Nature Publishing Group
Publishing Place London
Reviewing status
Grants SFB 1324
ERC CoG (HepatoMetabopath)
ERC POC (Faith)
Rainer Hoenig foundation
Horizon 2020 program HEPCAR
Helmholtz Future topic Inflammation and Immunology
Longfonds
European Union
EOS grant from the FNRS
Helmholtz Alliance 'Aging and Metabolic Programming, AMPro'
German Federal Ministry of Education and Research
German Center for Lung Research (DZL)
Helmholtz Association
R01HL141380
F32HL149290-01
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)