Editors' ChoicePhysiology

Limiting TGF-β signaling to prevent fibrosis

Sci. Signal.  17 Feb 2015:
Vol. 8, Issue 364, pp. ec34
DOI: 10.1126/scisignal.aaa9108

Fibrosis occurs when transforming growth factor–β (TGF-β) signaling is not attenuated after wound healing and fibroblasts remain activated, resulting in tissue scarring. The mechanisms that turn off TGF-β signaling after wound healing and inhibit this pathway in general are not well-understood. Palumbo-Zerr et al. noted that the abundance of the orphan receptor NR4A1 (nuclear receptor 4A1) was increased at the mRNA and protein levels in the fibrotic skin of patients with systemic sclerosis and in the skin of mice overexpressing a constitutively active TGF-β receptor type I (TBRI), which are a model for fibrosis. TGF-β stimulated the increased expression of NR4A1 through a complex containing the transcriptional effectors SMAD3, SMAD4, and SP1. Global Nr4a1 deficiency enhanced the expression of TGF-β target genes and fibrosis in mice overexpressing TBRI, as well as in other mouse models of fibrosis, including pulmonary fibrosis induced by bleomycin. Nr4a1-/- fibroblasts deposited more collagen and had greater expression of markers of myofibroblast differentiation in response to TGF-β compared to wild-type fibroblasts. TGF-β triggered the binding of NR4A1 to SP1 at SP1-binding sites in the promoter of COL1A1, which encodes a type I collagen. NR4A1-mediated repression of TGF-β target genes, including COL1A1, was reduced by knockdown of the transcriptional corepressors SIN3A (swi-independent-3 transcription regulator A) and REST corpressor-1, the histone deacetylase 1 (HDAC1), or the lysine-specific demethylase 1A (KDM1A; also known as LSD1). Phosphorylation of Ser351 inhibits NR4A1, and was higher in fibrotic human skin samples than in normal human skin samples. NR4A1 phosphorylation also increased with time in fibroblasts chronically exposed to TGF-β, and in the skin of mice overexpressing TBRI, an effect that required various histone deacetylases and AKT. Phosphorylated NR4A1 did not bind to SP1. The NR4A1 agonist Csn-B reduced the expression of TGF-β target genes and decreased skin fibrosis in mice overexpressing TBRI or pulmonary fibrosis in bleomycin-treated mice, as well as decreasing fibrosis in other mouse models. Thus, TGF-β signaling increases the expression of the gene encoding an inhibitor, a negative feedback loop that is attenuated in fibrotic diseases.

K. Palumbo-Zerr, P. Zerr, A. Distler, J. Fliehr, R. Mancuso, J. Huang, D. Mielenz, M. Tomcik, B. G. Fürnrohr, C. Scholtysek, C. Dees, C. Beyer, G. Krönke, D. Metzger, O. Distler, G. Schett, J. H. W. Distler, Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis. Nat. Med. 21, 150–158 (2015). [PubMed]