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NF-κB drives epithelial-mesenchymal mechanisms of lung fibrosis in a translational lung cell model
Patrick Sieber, … , Maxime Boucher, Oliver Nayler
Patrick Sieber, … , Maxime Boucher, Oliver Nayler
Published December 15, 2022
Citation Information: JCI Insight. 2023;8(3):e154719. https://doi.org/10.1172/jci.insight.154719.
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Research Article Cell biology Pulmonology

NF-κB drives epithelial-mesenchymal mechanisms of lung fibrosis in a translational lung cell model

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Abstract

In the progression phase of idiopathic pulmonary fibrosis (IPF), the normal alveolar structure of the lung is lost and replaced by remodeled fibrotic tissue and by bronchiolized cystic airspaces. Although these are characteristic features of IPF, knowledge of specific interactions between these pathological processes is limited. Here, the interaction of lung epithelial and lung mesenchymal cells was investigated in a coculture model of human primary airway epithelial cells (EC) and lung fibroblasts (FB). Single-cell RNA sequencing revealed that the starting EC population was heterogenous and enriched for cells with a basal cell signature. Furthermore, fractions of the initial EC and FB populations adopted distinct pro-fibrotic cell differentiation states upon cocultivation, resembling specific cell populations that were previously identified in lungs of patients with IPF. Transcriptomic analysis revealed active NF-κB signaling early in the cocultured EC and FB, and the identified NF-κB expression signatures were found in “HAS1 High FB” and “PLIN2+ FB” populations from IPF patient lungs. Pharmacological blockade of NF-κB signaling attenuated specific phenotypic changes of EC and prevented FB-mediated interleukin-6, interleukin-8, and CXC chemokine ligand 6 cytokine secretion, as well as collagen α-1(I) chain and α–smooth muscle actin accumulation. Thus, we identified NF-κB as a potential mediator, linking epithelial pathobiology with fibrogenesis.

Authors

Patrick Sieber, Anny Schäfer, Raphael Lieberherr, Silvia L. Caimi, Urs Lüthi, Jesper Ryge, Jan H. Bergmann, François Le Goff, Manuel Stritt, Peter Blattmann, Bérengère Renault, Patrick Rammelt, Bruno Sempere, Diego Freti, Rolf Studer, Eric S. White, Magdalena Birker-Robaczewska, Maxime Boucher, Oliver Nayler

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Figure 9

Expression of the NF-κB gene module in cell populations isolated from IPF patient lungs.

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Expression of the NF-κB gene module in cell populations isolated from IP...
(A) UMAP embedding of the Habermann et al. reference subset (5) comprising 36,901 epithelial and mesenchymal cells divided into control and ILD subsets. (B) Results of the module score analysis querying the Habermann reference human IPF patient lung cell atlas with the gene expression module TNF-α Signaling via NF-κB. The UMAP space of control and ILD cells is overlaid with the obtained module scores for each individual cell. Box plots display module scores (x axis) obtained for the respective reference cell populations (y axis) in control (red boxes) and ILD patient–derived (turquoise boxes) cells.

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