Background/Purpose: The ubiquitin-editing enzyme A20, encoded by TNFAIP3, is genetically implicated in autoimmune and inflammatory diseases. A20 plays a pivotal role in regulating inflammatory cellular pathways, and is tightly regulated by the downstream regulatory element antagonist modulator (DREAM) and other factors. Variants of TNFAIP3 are also associated with SSc and lung fibrosis in multi-ethnic cohorts. However, it remains unclear how genetic factors contribute to pathogenesis, and which cell types drive pathology due to SSc-specific genetic alterations. We therefore characterized the expression, function and role of A20 and DREAM in SSc and disease models

Methods: A20 and DREAM were measured in transcriptome datasets, skin and lung biopsies, and skin fibroblasts from SSc patients and healthy controls. The hypothesis that loss of A20 might play a direct pathogenic role in fibrosis was tested in A20 haploinsufficient mice that have reduced A20 comparable to humans harboring A20 risk alleles; and in mice with fibroblasts-specific deletion of A20 or DREAM. The role of A20 in myofibroblast transition was directly examined in skin and lung fibroblasts, dermal vascular endothelial cells (DMVE), adipose-derived stem cells (ADSC) and preadipocytes. A selective AdipoR1/R2 agonist was used to modulate A20 expression in skin fibroblasts and in vivo models of dermal fibrosis

Results: Unbiased transcriptome analysis of skin and lung biopsies indicated decreased A20 in SSc, whereas the negative A20 regulator DREAM was significantly elevated and anti-correlated with A20. In a variety of human and mouse mesenchymal cells, A20 potently inhibited profibrotic gene expression, myofibroblast transition and other fibrotic responses via blocking multiple SSc-linked signaling pathways. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulated major pathological and genomic features of SSc. In contrast, mice lacking DREAM (and showing elevated A20 expression) were protected from fibrosis. AdipoRon, an orally active small molecule targeting cellular adiponectin receptors, stimulated A20 expression in vitro in wild type but not in A20-deficient fibroblasts, potentially accounting for its anti-fibrotic activity

Conclusion: We provide first evidence that in addition to its well-established role in regulating inflammatory responses, A20 has a novel function in mitigating fibroblast activation. Together with DREAM, A20 thus constitutes a critical cell-intrinsic regulatory circuit governing fibrotic processes. Dysregulation of this circuit might be implicated in SSc pathogenesis, and represents a druggable target for fibrosis therapy

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-systemic-sclerosis-ssc-risk-gene-a20-tnfaip3-and-its-repressor-dream-determine-susceptibility-to-fibrosis/