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Updated: Aug 24, 2025
Murine Dermal Fibroblast Isolation by FACS
Published on: January 7, 2016
Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs
Wenxia Wang1, Swarna Bale1,2, Jun Wei1
1Northwestern Scleroderma Program, Department of Medicine, Feinberg School of Medicine, Chicago, IL, USA.
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.
Insights
Reduced A20, a ubiquitin-editing enzyme, and elevated DREAM drive fibrosis in systemic sclerosis (SSc). Restoring A20 function offers a novel therapeutic strategy for SSc-related fibrosis.
Area of Science:
- Immunology
- Genetics
- Fibrosis Research
Background:
- Variants in TNFAIP3 (A20) are linked to fibrosis in systemic sclerosis (SSc).
- The precise genetic mechanisms and cell types driving SSc pathogenesis remain unclear.
- Understanding the role of A20 and its regulator DREAM in SSc is crucial.
Purpose of the Study:
- To investigate the expression, function, and role of A20 and DREAM in SSc.
- To determine how genetic alterations in A20 and DREAM influence SSc pathogenesis.
- To explore potential therapeutic targets for SSc-related fibrosis.
Main Methods:
- Quantification of A20 and DREAM levels in SSc patient tissues (skin, lungs).
- Functional assays of A20 in isolated fibroblasts.
- Analysis of SSc disease models using A20-haploinsufficient and DREAM-null mice.
- Investigation of A20 regulation by TGF-β and response to an anti-fibrotic drug.
Main Results:
- A20 levels were decreased, while DREAM levels were increased in SSc skin and lungs.
- A20 demonstrated ex vivo anti-fibrotic activity in fibroblasts.
- A20 deficiency in mice recapitulated SSc pathology; DREAM deficiency conferred protection.
- An anti-fibrotic drug increased A20 expression, suggesting a therapeutic mechanism.
Conclusions:
- A20 possesses a cell-intrinsic function in limiting fibroblast activation.
- The A20-DREAM regulatory network is critical for controlling fibrotic processes in SSc.
- A20 and DREAM represent promising druggable targets for treating SSc fibrosis.
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