Gold compounds have a long history of use as immunosuppressants, but their precise mechanism of action is not completely understood. Using our recently developed liver-on-a-chip platform we now show that gold compounds containing planar N-heterocyclic carbene (NHC) ligands are potent ligands for the aryl hydrocarbon receptor (AHR). Further studies showed that the lead compound (MC3) activates TGFβ1 signaling and suppresses CD4+ T-cell activation in vitro, in human and mouse T cells. Conversely, genetic knockdown or chemical inhibition of AHR activity or of TGFβ1-SMAD-mediated signaling offsets the MC3-mediated immunosuppression. In scurfy mice, a mouse model of human immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, MC3 treatment reduced autoimmune phenotypes and extended lifespan from 24 to 58 days. Our findings suggest that the immunosuppressive activity of gold compounds can be improved by introducing planar NHC ligands to activate the AHR-associated immunosuppressive pathway, thus expanding their potential clinical application for autoimmune diseases.

中文翻译：

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NHC-金化合物通过在体外和在头皮屑小鼠中诱导 AHR-TGFβ1 信号传导来介导免疫抑制。

金化合物作为免疫抑制剂的使用历史悠久，但其确切的作用机制尚不完全清楚。使用我们最近开发的肝脏芯片平台，我们现在表明含有平面 N-杂环卡宾 (NHC) 配体的金化合物是芳烃受体 (AHR) 的有效配体。进一步的研究表明，先导化合物 (MC3) 在人和小鼠 T 细胞中激活 TGFβ1 信号传导并抑制 CD4+ T 细胞的体外激活。相反，AHR 活性或 TGFβ1-SMAD 介导的信号传导的基因敲低或化学抑制会抵消 MC3 介导的免疫抑制。在 Scurfy 小鼠（一种人类免疫失调性多发性内分泌病肠病 X 连锁综合征的小鼠模型）中，MC3 治疗减少了自身免疫表型，并将寿命从 24 天延长至 58 天。