LIGHT Is a Crucial Mediator of Airway Remodeling

Abstract

Chronic inflammatory airway diseases like asthma and chronic obstructive pulmonary disease are major health problems globally. Airway epithelial cells play important role in airway remodeling, which is a critical process in the pathogenesis of diseases. This study aimed to demonstrate that LIGHT, an inflammatory factor secreted by T cells after allergen exposure, is responsible for promoting airway remodeling. LIGHT increased primary human bronchial epithelial cells (HBECs) undergoing epithelial-mesenchymal transition (EMT) and expressing MMP-9. The induction of EMT was associated with increased NF-κB activation and p300/NF-κB association. The interaction of NF-κB with p300 facilitated NF-κB acetylation, which in turn, was bound to the promoter of ZEB1, resulting in E-cadherin downregulation. LIGHT also stimulated HBECs to produce numerous cytokines/chemokines that could worsen airway inflammation. Furthermore, LIGHT enhanced HBECs to secrete activin A, which increased bronchial smooth muscle cell (BSMC) migration. In contrast, depletion of activin A decreased such migration. The findings suggest a new molecular determinant of LIGHT-mediated pathogenic changes in HBECs and that the LIGHT-related vicious cycle involving HBECs and BSMCs may be a potential target for the treatment of chronic inflammation airway diseases with airway remodeling.

The TNF Family Molecules LIGHT and Lymphotoxin αβ Induce a Distinct Steroid-Resistant Inflammatory Phenotype in Human Lung Epithelial Cells

“…Understanding this signature may be important for future clinical studies aimed at identifying when LIGHT might be active during human asthma. Another aspect of LIGHT action implied in the aforementioned study of bronchial epithelial cells (44), and also suggested in a separate study of the A549 alveolar epithelial cell line (45), was that LIGHT has a major effect in promoting EMT. These authors showed that LIGHT down-regulated E-cadherin and moderately induced expression of vimentin, again in line with our results, but either did not assess (44), or did not convincingly demonstrate an action on (45), what we consider the cardinal features of EMT, namely induction of collagen, fibronectin, and alpha smooth muscle actin.…”

“…A recent study also partially addressed an inflammatory role for LIGHT in primary bronchial epithelial cells (44). The authors found induction of MMP-9, activin A, CXCL5, and CXCL8, and moderate induction of mRNA for CXCL1, 2, and 3, and ICAM-1, which is largely in line with our results.…”

Tumor necrosis factor family member LIGHT acts with IL‐1β and TGF‐β to promote airway remodeling during rhinovirus infection

“…Additional direct effects of LIGHT are also likely to be important. In vitro studies have found that LIGHT can promote some aspects of epithelial‐mesenchymal transition in lung epithelial cells such as downregulation of E‐cadherin and upregulation of fibronectin . Moreover, our recent studies suggest it can also drive proliferation of lung fibroblasts/myofibroblasts that could contribute to increases in smooth muscle mass (da Silva Antunes and Croft, unpublished).…”

Deducting MicroRNA-Mediated Changes Common in Bronchial Epithelial Cells of Asthma and Chronic Obstructive Pulmonary Disease—A Next-Generation Sequencing-Guided Bioinformatic Approach

“…Increasing evidence shows that bronchial epithelial cells orchestrate the pathobiological mechanisms in the pulmonary microenvironment, contributing to airway remodeling, a major pathophysiological change of chronic airway disease. Many studies have shown that bronchial epithelial cells produce inflammatory cytokines and promote proliferation and migration of bronchial smooth muscle cells [8,9,10].…”