Molecular mechanisms of aberrant remodelling in the pathogenesis of idiopathic pulmonary fibrosis

Abstract

Disruptions in tissue homeostasis and aberrant cell fate decisions are fundamental for the development of many chronic diseases, giving rise to a complex landscape of pathological changes. In the context of persistent injury conditions, such as those seen in idiopathic pulmonary fibrosis (IPF), cells have to adapt to a new equilibrium, often leading to aberrant remodelling and maladaptive cellular behaviours. Understanding these fundamental processes and underlying molecular mechanisms is crucial for unravelling the pathogenesis of IPF and exploring new research paths to ultimately identify therapeutic strategies for repair and regeneration of the fibrotic lung. Therefore, the present research aimed to explore key mechanisms governing aberrant cell fate decisions in IPF. Central to these findings is the role of aberrant epithelial remodelling, a process that has long remained a mystery. By leveraging a patient-derived 3D distal AO model, key IPF features, including the appearance of aberrant KRT5+ basal cells, were mimicked and found to be inducible within this model. Deeper characterisation of these aberrant basal cells revealed a metabolic alteration towards elevated O-linked β-N-acetylglucosamine (O-GlcNAc) levels and increased chromatin accessibility, particularly at promoter regions of metabolic and fibrotic genes with a JUNB motif. Combining these findings, an important role of O-GlcNAcylation of JUNB on its function was detected, fostering a profibrotic response to persistent injury, ultimately leading to aberrant epithelial remodelling. Importantly, perturbation of O-GlcNAc sites on JUNB mitigates the aberrant differentiation of basal cells and leads to a disruption of the fibrotic cell fate in general, eventually aiding in the restoration of homeostasis in the lung, specifically the alveolar lineage. This novel connection between metabolic dysregulation being transduced into chromatin alterations via the O-GlcNAc-JUNB-axis not only emphasises the importance for future investigations in the consequences of metabolic dysregulation in IPF but also opens up new avenues for therapeutic strategies to combat this fatal disease.