Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Bayern, Germany.
Ann Rheum Dis. 2021 Aug;80(8):1048-1056. doi: 10.1136/annrheumdis-2020-219822. Epub 2021 Apr 26.
X-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein with important functions in apoptosis, cellular differentiation and cytoskeletal organisation and is emerging as potential target for the treatment of various cancers. The aim of the current study was to investigate the role of XIAP in the pathogenesis of systemic sclerosis (SSc).
The expression of XIAP in human skin samples of patients with SSc and chronic graft versus host disease (cGvHD) and healthy individuals was analysed by quantitative PCR, immunofluorescence (IF) and western blot. XIAP was inactivated by siRNA-mediated knockdown and pharmacological inhibition. The effects of XIAP inactivation were analysed in cultured fibroblasts and in the fibrosis models bleomycin-induced and topoisomerase-I-(topoI)-induced fibrosis and in Wnt10b-transgenic mice.
The expression of XIAP, but not of other inhibitor of apoptosis protein family members, was increased in fibroblasts in SSc and sclerodermatous cGvHD. Transforming growth factor beta (TGF-β) induced the expression of XIAP in a SMAD3-dependent manner. Inactivation of XIAP reduced WNT-induced fibroblast activation and collagen release. Inhibition of XIAP also ameliorated fibrosis induced by bleomycin, topoI and overexpression of Wnt10b in well-tolerated doses. The profibrotic effects of XIAP were mediated via WNT/β-catenin signalling. Inactivation of XIAP reduces binding of β-catenin to TCF to in a TLE-dependent manner to block WNT/β-catenin-dependent transcription.
Our data characterise XIAP as a novel link between two core pathways of fibrosis. XIAP is overexpressed in SSc and cGvHD in a TGF-β/SMAD3-dependent manner and in turn amplifies the profibrotic effects of WNT/β-catenin signalling on fibroblasts via transducin-like enhancer of split 3. Targeted inactivation of XIAP inhibits the aberrant activation of fibroblasts in murine models of SSc.
凋亡抑制蛋白 X 连锁因子（XIAP）是一种多功能蛋白，在凋亡、细胞分化和细胞骨架组织中具有重要功能，并且正成为治疗各种癌症的潜在靶点。本研究旨在探讨 XIAP 在系统性硬化症（SSc）发病机制中的作用。
通过定量 PCR、免疫荧光（IF）和 Western blot 分析 SSc 患者和慢性移植物抗宿主病（cGvHD）患者及健康个体人皮肤样本中 XIAP 的表达。通过 siRNA 介导的敲低和药理学抑制来失活 XIAP。在培养的成纤维细胞中和在博来霉素诱导和拓扑异构酶 I（topoI）诱导的纤维化以及 Wnt10b 转基因小鼠中分析 XIAP 失活的影响。
XIAP 的表达增加，但凋亡抑制剂蛋白家族的其他成员的表达没有增加，在 SSc 和硬皮病 cGvHD 中的成纤维细胞中。转化生长因子-β（TGF-β）以 SMAD3 依赖的方式诱导 XIAP 的表达。XIAP 的失活减少了 WNT 诱导的成纤维细胞激活和胶原释放。在可耐受剂量下，抑制 XIAP 也改善了博来霉素、topoI 和 Wnt10b 过表达诱导的纤维化。XIAP 的促纤维化作用是通过 WNT/β-catenin 信号传导介导的。XIAP 的失活以 TLE 依赖的方式减少 β-catenin 与 TCF 的结合，从而阻断 WNT/β-catenin 依赖性转录。
我们的数据将 XIAP 描述为纤维化的两个核心途径之间的新联系。XIAP 在 SSc 和 cGvHD 中以 TGF-β/SMAD3 依赖的方式过表达，并通过转导素样增强子分裂 3 反式激活因子（TLE）反过来放大 WNT/β-catenin 信号对成纤维细胞的促纤维化作用。XIAP 的靶向失活抑制了 SSc 小鼠模型中成纤维细胞的异常激活。
