LIGHT-Lymphotoxin beta receptor activity regulates collagen synthesis in lung fibroblasts and is crucial for lung fibrosis in a mouse model of severe asthma 4641

Abstract Description Severe asthma is characterized by airway remodeling and peribronchial fibrosis. Fibroblasts produce collagen and other matrix proteins, but factors that are essential to drive fibroblast activity in asthma are not well understood. LIGHT/TNFSF14 deficient exhibit impaired fibrosis in severe asthma models, suggesting that signals through its receptor, LTβR, in lung fibroblasts might directly control collagen depositions. In this study, lung inflammation and fibrosis in mice with conditional deletion of LTβR in fibroblasts was assessed during an asthmatic response to house dust mite allergen. LTβR deletion in fibroblasts led to reduced numbers of CD4 T cells, macrophages and neutrophils in the lung following multiple challenges with allergen. Histological assessment showed significant reduction in cellular infiltration and collagen deposition in the lungs was almost ablated even though numbers of fibroblasts were unaltered. Human lung fibroblasts treated with TGFβ upregulated inflammatory and profibrotic transcripts when stimulated with LIGHT, including many collagen isoforms, COL4A1, COL4A2, COL8A2, and other inflammatory and fibrotic molecules namely TNFSF4, ACTA2, and MYH11. These results show that LTβR activity in fibroblasts is crucial for inflammatory and fibrotic activity and regulates peribronchiolar collagen deposition. LIGHT amplifies the effect of TGFβ and strongly drives a profibrotic phenotype in lung fibroblasts relevant for development of severe asthma. Funding Sources NIH U19 AI070535 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)