纤维化
生物
单倍率不足
肌成纤维细胞
癌症研究
免疫学
表型
医学
病理
基因
遗传学
作者
W. Wang,Bettina Schock,Hiam Abdala‐Valencia,Brian M. Jeong,Swarna Bale,Romy B. Christmann,Roberta Gonçalves Marangoni,Sergejs Berdnikovs,Erica L. Herzog,John Varga,Swati Bhattacharyya
标识
DOI:10.1016/j.jid.2020.03.818
摘要
Recent GWAS have uncovered consistent genetic linkage of SSc fibrotic phenotypes with TNFAIP3, encoding the ubiquitin-editing enzyme A20. A20 has been previously implicated in negative regulation of innate immunity, and hypomorphic A20 variants are associated with autoimmunity in SLE, RA,and others.The transcription factor DREAM binds to the A20 promoter to repress expression. Unbiased transcriptome analysis of skin and lung biopsies from SSc patients showed significantly decreased A20 levels and robust anti-correlation with fibrotic TGF-beta signaling. In contrast, the negative regulator of A20 DREAM was significantly elevated in SSc biopsies and anti-correlated with A20. In human skin and lung fibroblasts and ADSC, and mouse preadipocytes, A20 potently inhibited both profibrotic gene expression and myofibroblast transition via blocking multiple SSc-relevant pathways including canonical and non-canonical TGF-beta. We generated A20 haploinsufficient mice that, comparable to humans harboring A20 risk alleles, showed exaggerated organ fibrosis, and altered transcriptome profiles including enhanced fibrotic and inflammatory gene signatures. Furthermore,fibroblasts-specific deletion of A20 showed exaggerated fibrosis in mice. Conversely, DREAM-null mice were protected from organ fibrosis. Adiponectin elicited a sustained increase in A20 in fibroblasts whereas the anti-diabetic drug repaglinide, which blocks DREAM, enhanced A20 expression. Together, these studies uncover a novel role for A20 and DREAM as the primary checkpoints in modulating fibroblast activity in SSc. Implicating DREAM as a novel pathogenic factor in SSc could stimulate the discovery of drugs to block DREAM and enhance A20 function for the treatment of multiple organ fibrosis.
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