PU.1 controls fibroblast polarization and tissue fibrosis

Thomas Wohlfahrt, Simon Rauber, Steffen Uebe, Markus Luber, Alina Soare, Arif Ekici, Stefanie Weber, Alexandru-Emil Matei, Chih-Wei Chen, Christiane Maier, Emmanuel Karouzakis, Hans P. Kiener, Elena Pachera, Clara Dees, Christian Beyer, Christoph Daniel, Kolja Gelse, Andreas E. Kremer, Elisabeth Naschberger, Michael Stürzl, Falk Butter, Michael Sticherling, Susetta Finotto, Alexander Kreuter, Mark H. Kaplan, Astrid Jüngel, Steffen Gay, Stephen L. Nutt, David W. Boykin, Gregory M. K. Poon, Oliver Distler, Georg Schett, Jörg H. W. Distler and Andreas Ramming ()
Additional contact information
Thomas Wohlfahrt: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Simon Rauber: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Steffen Uebe: Institute of Human Genetics, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg
Markus Luber: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Alina Soare: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Arif Ekici: Institute of Human Genetics, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg
Stefanie Weber: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Alexandru-Emil Matei: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Chih-Wei Chen: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Christiane Maier: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Emmanuel Karouzakis: University Hospital Zurich
Hans P. Kiener: Medical University of Vienna
Elena Pachera: University Hospital Zurich
Clara Dees: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Christian Beyer: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Christoph Daniel: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg
Kolja Gelse: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Andreas E. Kremer: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Elisabeth Naschberger: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg
Michael Stürzl: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg
Falk Butter: Quantitative Proteomics Group, Institute of Molecular Biology
Michael Sticherling: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Susetta Finotto: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Alexander Kreuter: HELIOS St. Elisabeth Klinik Oberhausen, University Witten-Herdecke
Mark H. Kaplan: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine
Astrid Jüngel: University Hospital Zurich
Steffen Gay: University Hospital Zurich
Stephen L. Nutt: The Walter and Eliza Hall Institute of Medical Research, Molecular Immunology Division, Parkville
David W. Boykin: Georgia State University
Gregory M. K. Poon: Georgia State University
Oliver Distler: University Hospital Zurich
Georg Schett: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Jörg H. W. Distler: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen
Andreas Ramming: Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen

Nature, 2019, vol. 566, issue 7744, 344-349

Abstract: Abstract Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.

Date: 2019
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DOI: 10.1038/s41586-019-0896-x

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