Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs

Wenxia Wang, Swarna Bale, Jun Wei, Bharath Yalavarthi, Dibyendu Bhattacharyya, Jing Jing Yan, Hiam Abdala-Valencia, Dan Xu, Hanshi Sun, Roberta G. Marangoni, Erica Herzog, Sergejs Berdnikovs, Stephen D. Miller, Amr H. Sawalha, Pei-Suen Tsou, Kentaro Awaji, Takashi Yamashita, Shinichi Sato, Yoshihide Asano, Chinnaswamy Tiruppathi, Anjana Yeldandi, Bettina C. Schock, Swati Bhattacharyya () and John Varga ()
Additional contact information
Wenxia Wang: Feinberg School of Medicine
Swarna Bale: Feinberg School of Medicine
Jun Wei: Feinberg School of Medicine
Bharath Yalavarthi: University of Michigan
Dibyendu Bhattacharyya: University of Michigan
Jing Jing Yan: Feinberg School of Medicine
Hiam Abdala-Valencia: Northwestern University
Dan Xu: Northwestern University Feinberg School of Medicine
Hanshi Sun: University of Michigan
Roberta G. Marangoni: Feinberg School of Medicine
Erica Herzog: Yale University School of Medicine
Sergejs Berdnikovs: Northwestern University Feinberg School of Medicine
Stephen D. Miller: Northwestern University Feinberg School of Medicine
Amr H. Sawalha: University of Pittsburgh School of Medicine
Pei-Suen Tsou: University of Michigan
Kentaro Awaji: University of Tokyo Graduate School of Medicine
Takashi Yamashita: University of Tokyo Graduate School of Medicine
Shinichi Sato: University of Tokyo Graduate School of Medicine
Yoshihide Asano: University of Tokyo Graduate School of Medicine
Chinnaswamy Tiruppathi: University of Illinois
Anjana Yeldandi: Northwestern University
Bettina C. Schock: Queens University Belfast
Swati Bhattacharyya: Feinberg School of Medicine
John Varga: Feinberg School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33767-y

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