Journal Article

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

Tsou, Pei-Suen, Asano, Yoshihide, Yeldandi, Anjana, Bhattacharyya, Dibyendu, Abdala-Valencia, Hiam, Xu, Dan, Berdnikovs, Sergejs, Yan, Jing Jing, Sato, Shinichi, Marangoni, Roberta G., Wei, Jun, Herzog, Erica, Varga, John, Bale, Swarna, Awaji, Kentaro, Tiruppathi, Chinnaswamy, Bhattacharyya, Swati, Wang, Wenxia, Yamashita, Takashi, Yalavarthi, Bharath, Sun, Hanshi, Miller, Stephen D., Schock, Bettina C., Sawalha, Amr H.

2022

Overview

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. A20 gene variants are linked with systemic sclerosis (SS), but the mechanisms are unclear. Here, the authors show that A20 expression is reduced in SS skin and lungs, that its ablation in mice induces SS, and that show that fibrosis can be ameliorated by induction of A20.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/107 / 13/109 / 13/21 / 13/31 / 13/51 / 13/89 / 13/95 / 14 / 14/19 / 14/63 / 631/250/38 / 692/4023/1670/122/1801 / A20 protein / Ablation / Adiponectin / Animals / Bleomycin / Cells, Cultured / Disease Models, Animal / Fibroblasts / Fibroblasts - metabolism / Fibrosis / Genetic factors / Humanities and Social Sciences / Inflammatory diseases / Lungs / Mice / Mice, Knockout / multidisciplinary / Pathogenesis / Receptors, Adiponectin - metabolism / Science / Science (multidisciplinary) / Scleroderma / Scleroderma, Systemic - metabolism / Signal Transduction - genetics / Skin - pathology / Systemic sclerosis / Transforming Growth Factor beta - metabolism / Tumor Necrosis Factor alpha-Induced Protein 3 / Ubiquitin / Ubiquitins - metabolism