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

• Published in: Translational research : the journal of laboratory and clinical medicine 2016-12, Vol.183, p.71-86.e1
• Main Authors: Wei, Jun, Zhu, Hongyan, Lord, Gabriel, Bhattachayya, Mitra, Jones, Brielle M., Allaway, Graham, Biswal, Shyam S., Korman, Benjamin, Marangoni, Roberta G, Tourtellotte, Warren G., Varga, John
• Format: Article
• Language: English
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2016.12.002

The transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) governs anti-oxidant, 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 pharmacological 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 TGF-β-Smad signaling, while silencing Nrf2 resulted in constitutively elevated collagen synthesis, spontaneous myofibroblast differentiation and enhanced TGF-β responses. Bleomycin treatment of Nrf2-null mice resulted in exaggerated fibrosis. In wildtype mice, treatment with a novel pharmacological Nrf2 agonist 2-trifluoromethyl-2'-methoxychalone prevented dermal fibrosis induced by TGF-β. These findings are the first to identify Nrf2 as a cell-intrinsic anti- fibrotic factor with key roles in maintaining extracellular matrix homeostasis, and a pathogenic role in SSc. Pharmacological re-activation of Nrf2 therefore represents a novel therapeutic strategy toward effective treatment of fibrosis in SSc.