PDF(Pubmed)
Abstract：
The complexity of systemic lupus erythematosus (SLE) arises from intricate genetic and environmental interactions, with STING playing a pivotal role. This study aims to comprehend the function of STING using the pristane-induced lupus (PIL) model in Sting missense mutant mice (Goldenticket or StingGt), which contrasts with previous research using Sting knockout mice. Investigating two-month-old StingGt mice over six months post-PIL induction, we observed a profound reduction in autoimmune markers, including antinuclear and anti-dsDNA antibodies, germinal center B cells, and plasma cells, compared to their wild-type counterparts. A pivotal finding was the marked decrease in IL-17-producing T cells. Notably, the severity of lupus nephritis and pulmonary hemorrhages was significantly diminished in StingGt mice. These findings demonstrate that different genetic approaches to interfere with STING signaling can lead to contrasting outcomes in SLE pathogenesis, which highlights the need for a nuanced understanding of the role of STING in drug development for SLE. In summary, the loss of Sting function in Goldenticket mutant mice rescued autoimmune phenotypes in PIL. This study reveals the critical nature of STING in SLE, suggesting that the method of STING modulation significantly influences disease phenotypes and should be a key consideration in developing targeted therapies.
摘要：
系统性红斑狼疮（SLE）的复杂性源于复杂的遗传和环境相互作用，STING发挥了关键作用。本研究旨在了解STING在Sting错义突变小鼠（Goldenticket或StingGt）中使用pristane诱导的狼疮（PIL）模型的功能，这与以前使用Sting基因敲除小鼠的研究形成对比。研究两个月大的StingGt小鼠在PIL诱导后六个月，我们观察到自身免疫标志物的大幅减少，包括抗核和抗dsDNA抗体，生发中心B细胞，和浆细胞，与它们的野生型对应物相比。一个关键的发现是产生IL-17的T细胞的显著减少。值得注意的是,在StingGt小鼠中,狼疮性肾炎和肺出血的严重程度显著降低.这些发现表明，干扰STING信号的不同遗传方法可以导致SLE发病机制的不同结果。这凸显了对STING在SLE药物开发中的作用有细微差别的理解。总之,Goldenticket突变小鼠Sting功能的丧失拯救了PIL中的自身免疫表型。这项研究揭示了STING在SLE中的批判性，提示STING调制方法显著影响疾病表型,应成为开发靶向治疗的关键考虑因素.
