Genetic Deletion of Muc5b Reduces Interstitial Lung Disease in Neonatal Nedd4-2 Deficient Mice

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MUC5B has been implicated as a major risk factor for the development of idiopathic pulmonary fibrosis. However, insights into its role in the in vivo pathogenesis of interstitial lung disease (ILD) remain limited. We previously developed a mouse model for early onset ILD caused by congenital deletion of the ubiquitin ligase Nedd4-2 (Nedd4-2-/-). In this study, we introduced a lung-specific knockout of Muc5b (Muc5b-/-) in these mice (Nedd4-2-/-/Muc5b-/-) to investigate the in vivo role of Muc5b in the pathogenesis of early onset ILD. We compared the pulmonary phenotype of neonatal Nedd42/- mice to Muc5b-/-, Nedd4-2-/-/Muc5b-/- and control mice during the first month of life. We assessed survival, oxygen saturation and lung mechanics. Furthermore, we evaluated inflammation in bronchoalveolar lavage (BAL) and lung histology. Muc5b expression was investigated in BAL by western blots. Finally, we applied Imaging Mass Cytometry (IMC) for multiplexed spatial protein expression analysis on a single cell level. We found that neonatal Nedd4-2-/-/Muc5b-/- showed a reduced mortality (p<0.001) and improved pulmonary function compared to Nedd4-2-/- mice. Western blots revealed reduced Muc5b intensities in BAL of Nedd4-2-/-/Muc5b-/- versus Nedd4-2-/- mice (p=0.0012). Further, Muc5b deletion prevented airway mucus obstruction in Nedd4-2-/- mice which was accompanied by reduced concentrations of the inflammatory markers KC, IL-1β, IL-13, TNF-α and MIP-2 in the BAL of Nedd4-2-/-/Muc5b-/- mice. Lastly, IMC analysis revealed normalized Muc5b expression in airway epithelial cells, a reduction in inflammatory cells within the lung parenchyma, and lower mesenchymal marker expression. Taken together genetic deletion of Muc5b mitigates the severity of early onset ILD by preventing mucus obstruction in airways of neonatal Nedd4-2-/- mice. These data highlight the central role of Muc5b in the pathogenesis of ILD and its potential as therapeutic target in patients. Publication History Article published online: 28 February 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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