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.
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We thank D. Metzger and H. Ichinose for kindly providing us with Nr4a1fl/fl and αSma-Cre-ER mice. We thank M. Pascual Mate, R. Kleinlein, K. Dreißigacker and S. Fritz for excellent technical support. We also thank T. Kireva and E. Gianchecchi for their support in the study. We thank S. Wirtz and A. Weidemann for the expertise in experimental hepatic and kidney fibrosis. All figure drawings were adapted from Servier Medical Art. This study was supported by grants A40, A57, J20 and J29 of the Interdisciplinary Center for Clinical Research (IZKF) in Erlangen, individual grants from the German Research Foundation (Grants DI 1537/4-1, DI 1537/5-1, DI 1537/8-1, DI 1537/9-1 (Heisenberg Professorship), BE 5191/1-1, AK 144/1-1 and SCHE 1583/7-1), the SPP1468-IMMUNOBONE program of the German Research Foundation, the IMI-funded project BTCURE, the Metarthros project of the German Ministry of Education and Sciences and the project 00023728 from the Ministry of Health of the Czech Republic for conceptual development and SVV260031.
O. Distler has consultancy relationships and/or has received research funding from Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, Roche/Genentech, Medac, Biovitrium, Boehringer Ingelheim, Novartis, 4D Science, Active Biotec, Bayer, Sinoxa, Serodapharm, EpiPharm, GSK, Pharmacyclics and Biogen. J.H.W. Distler has consultancy relationships and/or has received research funding from Actelion, Active Biotech, Array Biopharma, Bayer Pharma, Boehringer Ingelheim, Celgene, GSK, JB Therapeutics, Novartis, Sanofi-Aventis, Sigma Tau and UCB in the area of potential treatments of SSc and is stock owner of 4D Science GmbH. 4D Science has a research cooperation with KaroBio on nuclear receptors as targets for anti-fibrotic therapies. All other authors declare no competing financial interests.
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Palumbo-Zerr, K., Zerr, P., Distler, A. et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis. Nat Med 21, 150–158 (2015). https://doi.org/10.1038/nm.3777
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