Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs.
Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs.
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DOI：
10.1038/s41467-022-33767-y
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发表时间：
2022-10-26
影响因子：
16.6
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中科院分区：
文献类型：
--
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除了自身免疫性和炎性疾病，编码泛素编辑酶A20的TNFAIP 3基因的变体也与系统性硬化症（SSc）中的纤维化相关。然而，目前尚不清楚遗传因素如何促进SSc发病机制，以及哪些细胞类型由于SSc特异性遗传改变而驱动疾病。因此，我们的特点的表达，功能和A20的作用，其负转录调节DREAM，在SSc患者和疾病模型。SSc皮肤和肺部的A20水平显著降低，而DREAM水平升高。在分离的成纤维细胞中，A20减轻离体促纤维化反应。A20单倍型不足或具有成纤维细胞特异性A20缺失的小鼠概括了SSc的主要病理学特征，而A20表达升高的DREAM缺失小鼠受到保护。与野生型成纤维细胞相比，在DREAM-null成纤维细胞中，TGF-β诱导A20的表达。靶向细胞脂联素受体的抗纤维化小分子刺激野生型成纤维细胞和博来霉素处理小鼠体外A20表达，但不刺激A20缺陷型成纤维细胞和博来霉素处理小鼠体外A20表达。因此，A20在抑制成纤维细胞活化方面具有新的细胞内在功能，并且与DREAM一起构成了控制SSc纤维化过程的关键调节网络。A20和DREAM代表了纤维化治疗的新型药物靶点。A20基因变异与系统性硬化症（SS）有关，但机制尚不清楚。在这里，作者表明，A20表达在SS皮肤和肺中减少，其在小鼠中的消融诱导SS，并且表明纤维化可以通过诱导A20来改善。
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.
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影响因子：
4.9
作者：
Fang F;Liu L;Yang Y;Tamaki Z;Wei J;Marangoni RG;Bhattacharyya S;Summer RS;Ye B;Varga J
通讯作者：
Varga J
影响因子：
3.7
作者：
Handoko L;Kaczkowski B;Hon CC;Lizio M;Wakamori M;Matsuda T;Ito T;Jeyamohan P;Sato Y;Sakamoto K;Yokoyama S;Kimura H;Minoda A;Umehara T
通讯作者：
Umehara T
影响因子：
4.9
作者：
Bhattacharyya S;Wang W;Graham LV;Varga J
通讯作者：
Varga J
影响因子：
13.6
作者：
Kim, Yaeni;Lim, Ji Hee;Park, Cheol Whee
通讯作者：
Park, Cheol Whee
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A