PU.1 controls fibroblast polarization and tissue fibrosis

Wohlfahrt T, Rauber S, Uebe S, Luber M, Soare A, Ekici AB, Weber S, Matei AE, Chen CW, Maier C, Karouzakis E, Kiener HP, Pachera E, Dees C, Beyer C, Daniel C, Gelse K, Kremer A, Naschberger E, Stürzl M, Butter F, Sticherling M, Finotto S, Kreuter A, Kaplan MH, Jüngel A, Gay S, Nutt SL, Boykin DW, Poon GM, Distler O, Schett G, Distler J, Ramming A (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Nature Nature Research

DOI: 10.1038/s41586-019-0896-x

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.

Authors with CRIS profile

Simon Rauber Department of Medicine 3 – Rheumatology and Immunology Steffen Uebe Institute of Human Genetics Arif Bülent Ekici Institute of Human Genetics Stefanie Weber Department of Medicine 3 – Rheumatology and Immunology Alexandru-Emil Matei Department of Medicine 3 – Rheumatology and Immunology Christiane Maier Professur für Molekulare und Experimentelle Chirurgie Clara Dees Department of Medicine 3 – Rheumatology and Immunology Christian Beyer Department of Medicine 3 – Rheumatology and Immunology Christoph Daniel Department of Nephropathology Andreas Kremer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Elisabeth Naschberger Medizinische Fakultät Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie Michael Sticherling Professur für Dermatologie Susetta Neurath-Finotto Department of Molecular Pneumology Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose Andreas Ramming Department of Medicine 3 – Rheumatology and Immunology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Medizinische Universität Wien AT Austria (AT) Carol Davila University of Medicine and Pharmacy / Universitatea de Medicină și Farmacie „Carol Davila” (UMF București) RO Romania (RO) Georgia State University US United States (USA) (US) Universität Witten/Herdecke DE Germany (DE) Walter and Eliza Hall Institute of Medical Research (WEHI) AU Australia (AU) Institut für Molekulare Biologie gGmbH / Institute of Molecular Biology (IMB) DE Germany (DE) Indiana University – Purdue University Indianapolis US United States (USA) (US)

How to cite

APA:

Wohlfahrt, T., Rauber, S., Uebe, S., Luber, M., Soare, A., Ekici, A.B.,... Ramming, A. (2019). PU.1 controls fibroblast polarization and tissue fibrosis. Nature. https://doi.org/10.1038/s41586-019-0896-x

MLA:

Wohlfahrt, Thomas, et al. "PU.1 controls fibroblast polarization and tissue fibrosis." Nature (2019).

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