The GIGA contributed to a study published in Nature on Chronic Obstructive Pulmonary Disease

Two research laboratories from the GIGA (Dr. Emmanuel Dejardin) and from the CIRM (Prof. Bernard Pirotte) contributed to a study published in Nature on Chronic Obstructive Pulmonary Disease (COPD).

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n collaboration with the research groups of Dr. Mathias Heikenwalder (DKFZ, Heidelberg) and Dr. Ali Onder Yildirim (DZL, München), Emmanuel Dejardin’s lab found that mice chronically exposed to cigarette smoke display an elevated activation of the Lymphotoxin-beta receptor (LTbR) and the inflammatory NF-kB signaling pathways, likewise in patients with smoking associated COPD¹. A set of multidisciplinary approaches from the different research groups combining transcriptomic, biochemical and histological analyses allowed identifying specific cell types and signaling pathways linked to the pathology. Based on previous published work from Dejardin’s lab^2–4, the authors demonstrated that exacerbated LTbR activation leads to tertiary lymph node (iBALT) development, lung fibrosis and death of alveolar epithelial progenitor cells. Noteworthy, the authors highlighted a link between the alternative/non-canonical NF-kB pathway and the WNT/b-catenin pathway ensuring the regeneration of alveolar epithelial cells. Thanks to the synthesis of a NIK kinase inhibitor by the Pirotte’s lab, Dejardin’s lab could show that activation of NIK represses the expression of b-catenin and the regenerative function in alveolar epithelial cells. In vivo, blockade of LTbR activation reduces the phenotypic features of COPD in mice, offering new possibilities for the treatment of human COPD patients.

This study has been performed and funded in the frame of the EOS (MODEL-IDI, No.30826052) awarded to Dejardin’s lab (ULiege) and Heikenwalder’s lab (DKFZ, Heidelberg) by the FNRS/FWO agency.

References

1. Conlon, T. M. et al. Inhibition of LTβR signalling activates WNT-induced regeneration in lung. Nature (2020). doi:10.1038/s41586-020-2882-8
2. Dejardin, E. et al. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kB pathways. Immunity 17, 525–535 (2002).
3. Ganeff, C. et al. Induction of the alternative NF-κB pathway by lymphotoxin αβ (LTαβ) relies on internalization of LTβ receptor. Mol. Cell. Biol. 31, (2011).
4. Boutaffala, L. et al. NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis. Cell Death Differ. 22, (2015).