Orphan nuclear receptor NR4A1 regulates transforming growth factor-? signaling and fibrosis

Palumbo-Zerr K, Zerr P, Distler A, Fliehr J, Mancuso R, Huang J, Mielenz D, Tomcik M, Fuernrohr BG, Scholtysek C, Dees C, Beyer C, Krönke G, Metzger D, Distler O, Schett G, Distler J (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Nature Medicine Nature Publishing Group

Book Volume: 21

Pages Range: 150-8

Journal Issue: 2

DOI: 10.1038/nm.3777

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-? (TGF-?) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-? target genes, thereby limiting pro-fibrotic TGF-? effects. Even though temporary upregulation of TGF-? in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-? 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-? signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.

Authors with CRIS profile

Pawel Zerr Department of Medicine 3 – Rheumatology and Immunology Dirk Mielenz Medizinische Fakultät Clara Dees Department of Medicine 3 – Rheumatology and Immunology Christian Beyer Department of Medicine 3 – Rheumatology and Immunology Gerhard Krönke Professur für Translationale Immunologie Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Involved external institutions

Université de Strasbourg (UDS) FR France (FR) Universitätsspital Zürich (USZ) CH Switzerland (CH)

How to cite

APA:

Palumbo-Zerr, K., Zerr, P., Distler, A., Fliehr, J., Mancuso, R., Huang, J.,... Distler, J. (2015). Orphan nuclear receptor NR4A1 regulates transforming growth factor-? signaling and fibrosis. Nature Medicine, 21(2), 150-8. https://doi.org/10.1038/nm.3777

MLA:

Palumbo-Zerr, Katrin, et al. "Orphan nuclear receptor NR4A1 regulates transforming growth factor-? signaling and fibrosis." Nature Medicine 21.2 (2015): 150-8.

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