Postdoctoral Fellow La Jolla Institute for Immunology La Jolla, California, United States
Introduction/Rationale: Pulmonary fibrosis is a hallmark of severe asthma and other chronic lung diseases and is driven by fibroblast-mediated production of collagen and extracellular matrix components. However, the key signals that regulate fibroblast activation and fibrotic remodeling remain poorly defined. Previous studies have shown that animals lacking TNFSF14 exhibit reduced lung fibrosis, indicating that signaling through its receptor, LTβR, may play a direct role in controlling collagen deposition.
Methods: This study investigated the role of fibroblast-specific LTβR signaling in allergen-induced lung fibrosis. Mice with tamoxifen-inducible, fibroblast-specific deletion of LTβR were used to assess fibrotic responses during experimental asthma. In parallel, recombinant LIGHT was used to stimulate cytokine-primed human pulmonary fibroblasts (TGFβ, IL-17, or IL-13) to determine whether LTβR signaling directly regulates fibrotic activity.
Results: Conditional deletion of LTβR in fibroblasts resulted in an almost complete loss of collagen deposition in the lungs following repeated allergen exposure, despite minimal changes in fibroblast accumulation. Consistent with this finding, LIGHT/TNFSF14 strongly induced expression of genes associated with fibrosis and cytoskeletal remodeling in cytokine-primed human pulmonary fibroblasts, including multiple collagen isoforms (COL1A1, COL1A2, COL3A1, COL5A1) and other matrisome-related genes (FN1, TAGLN, ACTA2, SPARC, FLNA). Importantly, this fibrotic transcriptional signature was also detected in fibroblasts isolated from patients with interstitial lung disease. Additionally, LTβR deletion in fibroblasts significantly reduced lung infiltration by neutrophils, macrophages, and T cells, likely due to impaired LIGHT–LTβR–dependent regulation of chemokines and adhesion molecules involved in immune cell recruitment.
Conclusion: LTβR signaling in fibroblasts is a critical driver of both fibrotic remodeling and inflammatory cell recruitment in severe and chronic lung disease.
