Ectopic expression of MUC5B in the respiratory bronchiole initiates endoplasmic reticulum stress in the IPF lung

IPF is an irreversible and progressive type of lung fibrosis that is pathologically characterized as spatially heterogeneous. Despite the identified dominant risk factor for IPF as the gain-of-function MUC5B promoter variant, little is understood for how MUC5B drives lung fibrosis.

We used spatial transcriptomics from idiopathic pulmonary fibrosis (IPF) and unaffected control lung tissue to further understand the pathogenesis of MUC5B-driven lung fibrosis.

We captured 43 fields of view in 15 IPF and 13 controls with and without the MUC5B promoter variant using the CosMx® platform and identified 19 cell types via semi-supervised clustering.

MUC5B was ectopically expressed in AT2 cells in controls with the risk variant. We observed a decreased proportion of AT2 cells in controls and an increased proportion of aberrant basaloid cells in IPF associated with the MUC5B risk variant. We identified co-localized expression of MUC5B in respiratory bronchioles with 13 genes including the endoplasmic reticulum (ER) stress marker XBP1 and distal secretory markers SCGB3A1 and SCGB1A1. Experimentally, we demonstrated a direct relationship between MUC5B expression and ER stress in bronchiolar epithelia in vitro and validated the co-expression of MUC5B and XBP1 in the IPF lung.

Based on our results, we conclude that MUC5B injures alveolar and bronchiolar epithelia that results in loss of AT2 cells and an increase in aberrant basaloid cells which initiates ER stress and a secretory phenotype in the terminal respiratory bronchiole, establishing a persistently injured distal airspace.