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.
GrantsSFB 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)