Abstract：
Regulatory T cell (Treg) deficiency leads to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which is a CD4+ T cell-driven autoimmune disease in both humans and mice. Despite understanding the molecular and cellular characteristics of IPEX syndrome, new treatment options have remained elusive. Here, we hypothesized that salvianolic acid B (Sal B), one of the main active ingredients of Salvia miltiorrhiza, can protect against immune disorders induced by Treg deficiency. To examine whether Sal B can inhibit Treg deficiency-induced autoimmunity, Treg-deficient scurfy (SF) mice with a mutation in forkhead box protein 3 were treated with different doses of Sal B. Immune cells, inflammatory cell infiltration, and cytokines were evaluated by flow cytometry, hematoxylin and eosin staining and enzyme-linked immunosorbent assay Kits, respectively. Moreover, RNA sequencing, western blot, and real-time PCR were adopted to investigate the molecular mechanisms of action of Sal B. Sal B prolonged lifespan and reduced inflammation in the liver and lung of SF mice. Moreover, Sal B decreased plasma levels of several inflammatory cytokines, such as IL-2, IFN-γ, IL-4, TNF-α, and IL-6, in SF mice. By analyzing the transcriptomics of livers, we determined the signaling pathways, especially the IL-2-signal transducer and activator of transcription 5 (STAT5) signaling pathway, which were associated with Treg deficiency-induced autoimmunity. Remarkably, Sal B reversed the expression of gene signatures related to the IL-2-STAT5 signaling pathway in vitro and in vivo. Sal B prolongs survival and inhibits lethal inflammation in SF mice through the IL-2-STAT5 axis. Our findings may inspire novel drug discovery efforts aimed at treating IPEX syndrome.
摘要：
调节性T细胞（Treg）缺乏导致免疫失调，多内分泌病,肠病,和X连锁（IPEX）综合征，在人类和小鼠中都是CD4+T细胞驱动的自身免疫性疾病。尽管了解IPEX综合征的分子和细胞特征，新的治疗方案仍然难以捉摸。这里,我们假设丹酚酸B(SalB)，丹参的主要活性成分之一，可以预防Treg缺乏引起的免疫紊乱。为了检查SalB是否可以抑制Treg缺乏引起的自身免疫，用不同剂量的SalB处理具有叉头框蛋白3突变的Treg缺陷型surfy(SF)小鼠。炎性细胞浸润，和细胞因子通过流式细胞术进行评估，苏木精和伊红染色和酶联免疫吸附试验试剂盒,分别。此外，RNA测序，westernblot,采用实时荧光定量PCR技术研究了SalB的作用分子机制。SalB延长了SF小鼠的寿命，减轻了肝脏和肺部的炎症。此外，SalB降低了几种炎性细胞因子的血浆水平，如IL-2，IFN-γ，IL-4,TNF-α,和IL-6，在SF小鼠。通过分析肝脏的转录组学，我们确定了信号通路，特别是IL-2信号转导和转录激活因子5（STAT5）信号通路，与Treg缺乏诱导的自身免疫有关。值得注意的是,SalB在体外和体内逆转了与IL-2-STAT5信号通路相关的基因标记的表达。SalB通过IL-2-STAT5轴延长SF小鼠的存活并抑制致死性炎症。我们的发现可能会激发旨在治疗IPEX综合征的新型药物发现工作。
