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| Status |
Public on Jul 10, 2020 |
| Title |
Inhibition of LTβR-signalling blocks epithelial apoptosis and activates endogenous Wnt-induced regeneration |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Lymphotoxin β-receptor-signalling orchestrates lymphoid neogenesis and subsequent tertiary lymphoid structures (TLS) associated with severe chronic inflammatory diseases spanning multiple organ systems. How LTβR-signalling drives chronic tissue damage particularly in the lung, which mechanism(s) regulate this process, and whether LTβR-blockade might be of therapeutic value has remained unclear. Here we demonstrate increased lymphotoxin expression of LTbR-ligands on myeloid and adaptive and innate immune-cells, enhanced non-canonical NF-κB signalling and enrichment of LTβR-target gene expression in epithelial cells of lungs from patients and mice with smoking-associated chronic obstructive pulmonary disease (COPD). Accordingly, Therapeutic inhibition of LTβR-signalling in young and aged mice with COPD disrupted TLS, reverted lung tissue destruction, airway-fibrosis and systemic muscle wasting. Mechanistically, we identified that LTβR-signalling blockade leads to diminished cell-death, concomitantly reactivated endogenous Wnt/β-catenin-signalling in alveolar epithelial cells and reduced TGFβ-signalling in airways. These findings highlight LTβR as a viable therapeutic target against TLS induced tissue damage that translates into novel anti-inflammatory, regenerative strategies to treat COPD.
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| Overall design |
Expression data of mice exposed to either filtered air or cigarette smoke or cigarette smoke plus LTβR-Ig fusion protein
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| Contributor(s) |
Conlon TM, John-Schuster G, Heide D, Prokosch S, Hetzer J, Fernandez IE, Verleden SE, Lopez M, Alsafadi H, Günes G, Jazi MZ, Hirani D, Burgstaller G, Becker L, Irmler M, Beckers J, Wagner D, O´Connor T, Dejardin E, Eickelberg O, Königshoff M, Heikenwalder M, Yildirim AO |
| Citation(s) |
24898581, 33149305 |
| Submission date |
Jan 23, 2019 |
| Last update date |
Dec 08, 2020 |
| Contact name |
Johannes Beckers |
| E-mail(s) |
johannes.beckers@helmholtz-munich.de
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| Organization name |
Helmholtz Zentrum Muenchen
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| Department |
Institute of Experimental Genetics
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| Street address |
Ingolstaedter Landstr. 1
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| City |
Neuherberg |
| ZIP/Postal code |
85764 |
| Country |
Germany |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (27)
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| Relations |
| BioProject |
PRJNA516667 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE125521_Non-normalized_data.txt.gz |
1.6 Mb |
(ftp)(http) |
TXT |
| GSE125521_RAW.tar |
3.1 Mb |
(http)(custom) |
TAR |
| Processed data included within Sample table |
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