Therapeutic targeting of iBALT induces lung regeneration in COPD

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, with limited therapeutic options available, and no treatment able to reverse disease progression. Importantly, immune cells infiltrating the COPD lung are organized into inducible bronchus-associated lymphoid tissue (iBALT), which drives emphysema progression in humans and mice. iBALT formation requires the interaction of lymphotoxin β receptor (LTβR) on stromal organizer cells with TNF superfamily members lymphotoxin α (LTα) and β (LTβ). Here we investigate the therapeutic potential of iBALT-blockade in COPD pathogenesis. Gene set enrichment analysis (GSEA) of transcriptomics data and qPCR of an independent cohort revealed enrichment of the LTβR signaling pathway in the lungs of COPD patients resulting in increased expression of chemokines like CXCL13. Similar to COPD patients, mice chronically exposed to CS demonstrated iBALT generation and emphysema. Interestingly, LTβR-Ig treatment impaired CS-induced iBALT generation concomitant with the down regulation of chemokines like Cxcl13 and Ccl19. Remarkably, this led to full reversal of emphysema and regression of CS-mediated airway remodeling, which was accompanied by improvement in muscle wasting a prominent comorbidity of COPD. Mechanistically, lung restoration by LTβR-signalling-blockade was accompanied by increased Wnt/beta-catenin signal activity, which was crucial for lung epithelial regeneration. Of physiological relevance, this was validated in primary alveolar epithelial cells, human lung organoids and 3D human precision cut lung slices. Our findings pave the way for therapeutically exploiting the LTβR signalling pathway as a novel approach for activating Wnt signalling and tissue regeneration in chronic inflammatory diseases.