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

Autor: Graham Allaway, Brielle Jones, Roberta Goncalves Marangoni, Hongyan Zhu, Mitra Bhattachayya, Warren G. Tourtellotte, Gabriel Lord, Shyam Biswal, Jun Wei, John Varga, Benjamin D. Korman
Rok vydání: 2017
Předmět:
0301 basic medicine
Agonist
NF-E2-Related Factor 2
medicine.drug_class
Down-Regulation
Biology
digestive system
environment and public health
Article
Bleomycin
Mice
03 medical and health sciences
Chalcones
0302 clinical medicine
Transforming Growth Factor beta
Fibrosis
Physiology (medical)
medicine
Animals
Humans
Gene silencing
Genetic Predisposition to Disease
RNA
Messenger
Oleanolic Acid
Transcription factor
Cells
Cultured
Mice
Knockout
Scleroderma
Systemic
integumentary system
Biochemistry (medical)
Public Health
Environmental and Occupational Health
General Medicine
Transforming growth factor beta
Fibroblasts
respiratory system
medicine.disease
030104 developmental biology
Gene Expression Regulation
030220 oncology & carcinogenesis
Immunology
Cancer research
TLR4
biology.protein
Myofibroblast
Transforming growth factor
Zdroj: Transl Res
ISSN: 1931-5244
DOI: 10.1016/j.trsl.2016.12.002
Popis: 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.
Databáze: OpenAIRE
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