TY - JOUR
T1 - Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs
AU - Wang, Wenxia
AU - Bale, Swarna
AU - Wei, Jun
AU - Yalavarthi, Bharath
AU - Bhattacharyya, Dibyendu
AU - Yan, Jing Jing
AU - Abdala-Valencia, Hiam
AU - Xu, Dan
AU - Sun, Hanshi
AU - Goncalves Marangoni, Roberta
AU - Herzog, Erica
AU - Berdnikovs, Sergejs
AU - Miller, Stephen D
AU - Sawalha, Amr H.
AU - Tsou, Pei Suen
AU - Awaji, Kentaro
AU - Yamashita, Takashi
AU - Sato, Shinichi
AU - Asano, Yoshihide
AU - Tiruppathi, Chinnaswamy
AU - Yeldandi, Anjana
AU - Schock, Bettina C.
AU - Bhattacharyya, Swati
AU - Varga, John
N1 - Funding Information:
We are grateful to members of the Scleroderma Research Laboratory, the staff of the Mouse Histology & Phenotyping Laboratory (MHPL), and the Northwestern University Skin Diseases Research and Imaging Cores for excellent technical support. We acknowledge the unreserved support from Dr Carol Feghali-Bostwick for providing lung biopsy specimens collected from SSc-ILD transplant biopsies and Jose Naranjo for providing an antisense-DREAM plasmid. The study was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS AR42309), and the Scleroderma Foundation.
Funding Information:
We are grateful to members of the Scleroderma Research Laboratory, the staff of the Mouse Histology & Phenotyping Laboratory (MHPL), and the Northwestern University Skin Diseases Research and Imaging Cores for excellent technical support. We acknowledge the unreserved support from Dr Carol Feghali-Bostwick for providing lung biopsy specimens collected from SSc-ILD transplant biopsies and Jose Naranjo for providing an antisense-DREAM plasmid. The study was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS AR42309), and the Scleroderma Foundation.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.
AB - In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.
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U2 - 10.1038/s41467-022-33767-y
DO - 10.1038/s41467-022-33767-y
M3 - Article
C2 - 36289219
AN - SCOPUS:85140614613
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6358
ER -