Introduction: Targeting the IL-33 pathway has shown clinical benefit in asthma and COPD, but the mechanism by which it modulates airway diseases is not well-understood. Here, we explore the role of IL-33 in pro-fibrotic pathways and lung remodeling using human structural cells and relevant mouse models.
Methods: Human structural cells were stimulated with IL-33 and differential gene expression was assessed by RNAseq. Intranasal administration of IL-33 was used for specific lung delivery. Pro-fibrotic pathways and remodeling features were assessed in the lung by bulk RNAseq, Taqman, Luminex and histology. Airway remodeling was assessed in a mouse model of HDM-induced lung inflammation in the presence of anti-IL-33 (itepekimab).
Results and conclusion: IL-33 stimulation of structural cells induced expression of pro-fibrotic mediators and pathways associated with remodeling. To interrogate these effects in vivo, IL-33 was administered Intranasally for 4 days, which resulted in lung inflammation comprised of several type 1 and type 2 cytokines along with goblet cell metaplasia and induction of genes associated with fibrosis, including Mmp12, Muc5ac, Col1a1, Fn1, Tgfb1 and Serpinh1. To further study the role of IL-33 in fibrosis in vivo, we used a mouse model of airway inflammation induced by repeated Intranasal administration of HDM, which significantly increased lung immune cell infiltration and airway remodeling, including mucus plugging and consolidation. Therapeutic intervention with anti-IL-33 (itepekimab) inhibited airway remodeling and lung inflammation, providing direct evidence for the role of IL-33 in airway fibrosis and inflammation.