ZAC-1 regulates TGFβ-dependent fibroblast activation in fibrotic diseases by modulation of AP-1 signaling

细胞外基质过度沉积，扰乱生理组织结构，损害受累器官的生理功能。纤维化组织重塑给现代社会造成了重大负担，据估计，发达国家高达45%的死亡是由纤维化组织重塑造成的。SSc和其他纤维化疾病的特征是成纤维细胞不受控制的持续激活。这些肌成纤维细胞继续释放过量的细胞外基质，导致细胞外基质的过度积累和进行性组织纤维化。虽然已经确定了几种成纤维细胞激活的介质，如转化生长因子-β (tgf -β)，但它们如何驱动成纤维细胞的慢性激活和进行性组织重塑仍然知之甚少。我们的初步结果提供了第一个证据，证明锌指转录因子Zac-1协调了一个正反馈回路，放大了纤维化中的TGFβ信号。TGFβ上调Zac-1在SSc中的表达。Zac-1反过来增强TGFβ对成纤维细胞的刺激作用，促进成纤维细胞向肌成纤维细胞的转化和胶原的释放，并加剧实验性纤维化。在体内和体外，敲低Zac-1可改善TGFβ的促纤维化作用。从机制上讲，Zac-1似乎通过促进AP-1激活来放大tgf - β的纤维化作用。为了进一步表征Zac-1在纤维化疾病发病机制中的作用，我们现在的目标是：将Zac-1的表达水平和模式与SSc和其他纤维化疾病患者的临床特征联系起来，2)更详细地解读Zac-1对成纤维细胞的调节作用，3)在类似SSc不同亚群和阶段的其他小鼠模型中分析Zac-1的纤维化，4)阐明AP-1信号通路在Zac-1扩增环中的功能作用和调控。这些数据可能确定Zac-1是SSc抗纤维化治疗的靶点。

excessive deposition of extracellular matrix with perturbation of the physiological tissue architecture and impairment the physiological function of the affected organs. Fibrotic tissue remodeling imposes a major burden on modern societies and has been estimated to contribute to up to 45% of deaths in the developed world. SSc and other fibrotic diseases are characterized by an uncontrolled, persistent activation of fibroblasts. These myofibroblasts continue to release excessive amounts of extracellular matrix, which leads to excessive accumulation of extracellular matrix and progressive tissue fibrosis. Although several mediators of fibroblast activation such as transforming growth factor-β (TGFβ) have been identified, it remains poorly understood, how they drive the chronic activation of fibroblasts and the progressive tissue remodelling. Our preliminary results provide first evidence that the zinc finger transcription factor Zac-1 orchestrates a positive feedback loop that amplifies TGFβ signaling in fibrosis. TGFβ upregulates the expression of Zac-1 in SSc. Zac-1 in turn enhances the stimulatory effects of TGFβ on fibroblasts, promotes fibroblast-to-myofibroblast transition and collagen release and exacerbates experimental fibrosis. Knockdown of Zac-1 ameliorates the profibrotic effects of TGFβ in vitro and in vivo. Mechanistically, the Zac-1 seems to amplify the profibrotic effects of TGFβ by promoting AP-1 activation. To further characterize the role of Zac-1 in the pathogenesis of fibrotic diseases, we now aim to: 1.) Correlate the expression levels and patterns of Zac-1 with clinical characteristics of patients with SSc and other fibrotic diseases, 2.) decipher the regulatory effects of Zac-1 on fibroblasts in more detail, 3.) analyse the profibrotic of Zac-1 in additional murine models resembling different subgroups and stages of SSc and 4.) unravel the functional role and the regulation of AP-1 signaling in the Zac-1 amplification loop. These data may establish Zac-1 as a target for antifibrotic therapies in SSc.