Nrf2 exerts cell-autonomous antifibrotic effects: compromised function in systemic sclerosis and therapeutic rescue with a novel heterocyclic chalcone derivative.

Abstract

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) governs antioxidant, innate immune and cytoprotective responses and its deregulation is prominent in chronic inflammatory conditions. To examine the hypothesis that Nrf2 might be implicated in systemic sclerosis (SSc), we investigated its expression, activity, and mechanism of action in SSc patient samples and mouse models of fibrosis and evaluated the effects of a novel pharmacologic Nrf2 agonist. We found that both expression and activity of Nrf2 were significantly reduced in SSc patient skin biopsies and showed negative correlation with inflammatory gene expression. In skin fibroblasts, Nrf2 mitigated fibrotic responses by blocking canonical transforming growth factor-β (TGF-β)-Smad signaling, whereas silencing Nrf2 resulted in constitutively elevated collagen synthesis, spontaneous myofibroblast differentiation, and enhanced TGF-ß responses. Bleomycin treatment of Nrf2-null mice resulted in exaggerated fibrosis. In wild-type mice, treatment with a novel pharmacologic Nrf2 agonist 2-trifluoromethyl-2'-methoxychalcone prevented dermal fibrosis induced by TGF-β. These findings are the first to identify Nrf2 as a cell-intrinsic antifibrotic factor with key roles in maintaining extracellular matrix homeostasis and a pathogenic role in SSc. Pharmacologic reactivation of Nrf2, therefore, represents a novel therapeutic strategy toward effective treatment of fibrosis in SSc.

• Authors: Jun Wei, Hongyan Zhu, Gabriel Lord, Mitra Bhattachayya, Brielle M Jones, Graham Allaway, Shyam S Biswal, Benjamin Korman, Roberta G Marangoni, Warren G Tourtellotte, John Varga
• Journal: Translational research : the journal of laboratory and clinical medicine (Transl Res) Vol. 183 Pg. 71-86.e1 (05 2017) ISSN: 1878-1810 [Electronic] United States
• PMID: 28027929 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
• 2-trifluoromethyl-2'-methoxychalone
• Chalcones
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Nfe2l2 protein, mouse
• RNA, Messenger
• Transforming Growth Factor beta
• Bleomycin
• Oleanolic Acid

Topics

• Animals
• Bleomycin (toxicity)
• Cells, Cultured
• Chalcones (pharmacology)
• Down-Regulation
• Fibroblasts (metabolism)
• Fibrosis (chemically induced, genetics, pathology)
• Gene Expression Regulation (drug effects, physiology)
• Genetic Predisposition to Disease
• Humans
• Mice
• Mice, Knockout
• NF-E2-Related Factor 2 (antagonists & inhibitors, genetics, metabolism)
• Oleanolic Acid (analogs & derivatives, chemistry, pharmacology)
• RNA, Messenger (genetics, metabolism)
• Scleroderma, Systemic (metabolism)
• Transforming Growth Factor beta (toxicity)