Inhibition of LTβR signalling activates WNT-induced regeneration in lung

Abstract

Summary Lymphotoxin β-receptor (LTβR)-signalling orchestrates lymphoid neogenesis and subsequent tertiary lymphoid structures (TLS) 1 , 2 , associated with severe chronic inflammatory diseases spanning multiple organ systems 3 – 6 . 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 expression of LTβR-ligands on adaptive and innate immune-cells, enhanced non-canonical NF-κB signalling and enriched LTβR-target gene expression in epithelial cells of lungs from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and mice exposed to chronic cigarette smoke. Therapeutic inhibition of LTβR-signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue (iBALT), induced lung tissue regeneration, and reverted airway-fibrosis and systemic muscle wasting. Mechanistically, LTβR-signalling blockade dampened epithelial non-canonical NF-κB activation, reduced TGFβ-signalling in airways, induced regeneration by preventing epithelial cell-death and by activating Wnt/β-catenin-signalling in alveolar epithelial progenitor cells. These findings highlight that LTβR-signalling inhibition represents a viable therapeutic option combining anti-TLS, anti-apoptotic with tissue regenerative strategies.

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

“…Like in many chronic diseases associated with ageing, this local lung microenvironment is insufficiently supportive for lung repair in COPD 1,4,5 . For example, studies have indicated that an imbalance of canonical and noncanonical WNT signaling results in impaired alveolar regeneration in COPD 4,6 .…”

X-ray Dark-Field Chest Imaging can Detect and Quantify Emphy-sema in COPD Patients

“…Providing detailed information on lung micromorphology, dark-field chest radiography could serve as a low-dose imaging tool enabling periodic examinations to resolve the prevalent condition of underdiagnosed COPD. In the context of recently reported advances in regenerative therapeutics, 40 dark-field imaging might support further translational research in this field and might at a later stage be integrated in disease management concepts for the monitoring of treatment response.…”

Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice

“…Morever, in the same model, administration of a cancer-specific antigen antibody–LTα fusion protein enhanced eradication of pulmonary metastasis via an improved T-cell response evoked by LTα-dependent induction of peripheral lymphoid tissue at the tumor site [ 23 ]. This effect, most likely, was due to LTαβ–LTβR interaction, since LTβR blockade abrogated the formation of tertiary lymphoid structures in the lungs [ 44 ]. In addition, LTα production by effector T cells was shown to potentiate an antitumor response in a B16F10 melanoma pulmonary metastasis model [ 45 ], while blocking LTβR with a neutralizing monoclonal antibody decreased effector T-cell cytotoxicity in vitro [ 46 ], suggesting that LTαβ–LTβR interaction was crucial for the cytotoxic cell activation required for tumor regression.…”

“…Increased LTβR mRNA levels in tumor, but not in normal, tissues were associated with a worse overall survival in patients with lung adenocarcinomas [ 47 ]. LTβR expression in the lungs correlated with inflammation, at least in COPD [ 44 ]; therefore, increased LTβR expression in tumors may enhance inflammation and promote tumor growth. Moreover, stimulation of LTβR may subsequently trigger downstream non-canonical NF-κB signaling via activation of NF-κB-inducing kinase (NIK), which is involved in metastatic gene upregulation [ 48 ].…”