title: Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis.
abstract: Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Fliehr
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Rossella
authors.initials: R
authors.lastname: Mancuso
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jingang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Centre, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Mielenz
authors.affiliation: 1] Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany. [2] Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.affiliation: 1] Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Centre, University of Erlangen-Nuremberg, Erlangen, Germany. [2] Division of Biological Chemistry, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Fürnrohr
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Scholtysek
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104/INSERM U 964, Université de Strasbourg, Illkirch, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Center for Research of Systemic Autoimmune Diseases, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D056970:Co-Repressor Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D012867:Skin / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014945:Wound Healing; D055815:Young Adult
chemical_list: D056970:Co-Repressor Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D016329:Sp1 Transcription Factor; D016212:Transforming Growth Factor beta; D056466:Histone Demethylases; D056284:Histone Deacetylase 1; D056264:Sin3 Histone Deacetylase and Corepressor Complex