TY - JOUR
T1 - Nrf2 exerts cell-autonomous antifibrotic effects
T2 - compromised function in systemic sclerosis and therapeutic rescue with a novel heterocyclic chalcone derivative
AU - Wei, Jun
AU - Zhu, Hongyan
AU - Lord, Gabriel
AU - Bhattachayya, Mitra
AU - Jones, Brielle M.
AU - Allaway, Graham
AU - Biswal, Shyam S.
AU - Korman, Benjamin
AU - Marangoni, Roberta G.
AU - Tourtellotte, Warren G.
AU - Varga, John
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health ( AR-42309 for J. Varga, AR-066418 for J. Varga and G. Allaway, AR-065800 for J. Wei, and OD-010945 and CA-060553 for W. G. Tourtellotte).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85009948909&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009948909&partnerID=8YFLogxK
U2 - 10.1016/j.trsl.2016.12.002
DO - 10.1016/j.trsl.2016.12.002
M3 - Article
C2 - 28027929
AN - SCOPUS:85009948909
SN - 1931-5244
VL - 183
SP - 71-86.e1
JO - Translational Research
JF - Translational Research
ER -