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ResearchIn-Press PreviewCell biologyPulmonology Open Access | 10.1172/jci.insight.154719

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

Patrick Sieber,1 Anny Schäfer,1 Raphael Lieberherr,2 Silvia L Caimi,3 Urs Lüthi,2 Jesper Ryge,4 Jan H. Bergmann,4 Francois Le Goff,5 Manuel Stritt,6 Peter Blattmann,4 Bérengère Renault,4 Patrick Rammelt,6 Bruno Sempere,6 Diego Freti,1 Rolf Studer,1 Eric S. White,7 Magdalena Birker-Robaczewska,1 Maxime Boucher,1 and Oliver Nayler1

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Sieber, P. in: JCI | PubMed | Google Scholar |

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Schäfer, A. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Lieberherr, R. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Caimi, S. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Lüthi, U. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Ryge, J. in: JCI | PubMed | Google Scholar |

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Bergmann, J. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Le Goff, F. in: JCI | PubMed | Google Scholar |

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Stritt, M. in: JCI | PubMed | Google Scholar |

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Blattmann, P. in: JCI | PubMed | Google Scholar |

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Renault, B. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Rammelt, P. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Sempere, B. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Freti, D. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Studer, R. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by White, E. in: JCI | PubMed | Google Scholar |

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Birker-Robaczewska, M. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Boucher, M. in: JCI | PubMed | Google Scholar

1Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

2HTS Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

3DD Cardiovascular and Fibrosis Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

4Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

5Analytical Sciences, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

6Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland

7Interstitial Lung Diseases, Boehringer Ingelheim Pharmaceuticals Ltd, Ridgefield, United States of America

Find articles by Nayler, O. in: JCI | PubMed | Google Scholar |

Published December 15, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.154719.
Copyright © 2022, Sieber et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 15, 2022 - Version history
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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 co–culture model of human primary airway epithelial cells (EC) and lung fibroblasts (FB). Single–cell RNA sequencing (sc–RNA–seq) 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 cell populations adopted distinct pro–fibrotic cell differentiation states upon co-cultivation, resembling specific cell populations that were previously identified in lungs of IPF patients. Transcriptomic analysis revealed active nuclear factor NF–kappa–B (NF–κB) signaling early in the co–cultured EC and FB cells and the identified NF–κB expression signatures were also 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 (IL6), interleukin–8 (IL–8) and C–X–C motif chemokine ligand 6 (CXCL6) cytokine secretion, as well as collagen alpha–1(I) chain (COL1A1) and alpha–smooth muscle actin (α–SMA) accumulation. Thus, we identified NF–κB as a potential mediator, linking epithelial pathobiology with fibrogenesis.

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graphical abstract
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  • Version 1 (December 15, 2022): In-Press Preview
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