Journal Article

PU.1 controls fibroblast polarization and tissue fibrosis

Finotto, Susetta, Karouzakis, Emmanuel, Schett, Georg, Luber, Markus, Matei, Alexandru-Emil, Jüngel, Astrid, Ekici, Arif, Beyer, Christian, Nutt, Stephen L., Kreuter, Alexander, Weber, Stefanie, Boykin, David W., Rauber, Simon, Maier, Christiane, Kremer, Andreas E., Butter, Falk, Pachera, Elena, Stürzl, Michael, Distler, Oliver, Distler, Jörg H. W., Daniel, Christoph, Dees, Clara, Kaplan, Mark H., Chen, Chih-Wei, Naschberger, Elisabeth, Poon, Gregory M. K., Gay, Steffen, Ramming, Andreas, Wohlfahrt, Thomas, Uebe, Steffen, Gelse, Kolja, Sticherling, Michael, Soare, Alina, Kiener, Hans P.

2019

Overview

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. The transcription factor PU.1 is an essential regulator of the pro-fibrotic gene expression program in fibroblasts; PU.1 expression is upregulated in various fibrotic diseases, whereas inactivation of PU.1 induces regression of fibrosis in a number of organs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/109 / 13/31 / 13/51 / 14/19 / 38/47 / 38/89 / 45/15 / 45/91 / 631/250 / 692/699/1670/122/1801 / 96/106 / Analysis / Animals / Arthritis / B cells / Base Sequence / Biochemistry / Bioinformatics / Cell Differentiation - genetics / Collagen / Deactivation / Disease / Enzymes / Epigenesis, Genetic / Epigenetics / Extracellular matrix / Female / Fibroblasts / Fibroblasts - metabolism / Fibroblasts - pathology / Fibrosis / Fibrosis - genetics / Fibrosis - pathology / Gene expression / Genes / Genomes / Genotype & phenotype / Homeostasis / Humanities and Social Sciences / Humans / Immune response / Inactivation / Inflammation / Inflammation - genetics / Inflammation - pathology / Male / Medical schools / Mice / MicroRNAs / Morphogenesis / multidisciplinary / Organs / Pharmacology / Phenotypes / Physiological aspects / Post-transcription / Promoter Regions, Genetic - genetics / Proto-Oncogene Proteins - antagonists & inhibitors / Proto-Oncogene Proteins - metabolism / PU.1 protein / Scars / Science / Science (multidisciplinary) / Trans-Activators - antagonists & inhibitors / Trans-Activators - metabolism / Transcription (Genetics) / Transcription factors / Tumor necrosis factor-TNF / Variance analysis