Role of the long non-coding RNA lincRNA-LUCAT1 in a murine model of systemic lupus erythematosus

长非编码RNA lincRNA-LUCAT1在系统性红斑狼疮小鼠模型中的作用

• 批准号: 418082105
• 负责人: Dr. Tim Vierbuchen
• 金额: --
• 依托单位: Forschungszentrum Borstel - Leibniz Lungenzentrum
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418082105?language=en
• 关键词: Role; long; non; coding; RNA

The immune system has evolved to defend the body from invading pathogens and abnormal endogenous cells while healthy cells should be protected from excessive immune responses. Therefore, a tight regulation of immune reactions is fundamental. Recent studies have shown that besides proteins and microRNAs, long non-coding RNAs (lncRNAs) possess an important role in the regulation of immune genes. However, the function of most lncRNAs and their role in inflammatory diseases remains elusive. The long intergenic non-coding RNA LUCAT1 (lincRNA-LUCAT1) is upregulated after activation of several innate immune receptors and negatively regulates the expression of pro-inflammatory and interferon stimulated genes. Human phagocytes deficient in LUCAT1 show significantly increased expression of immune regulated genes particularly interferon-stimulated genes (ISGs) after stimulation while overexpression of LUCAT1 in THP1 or pulmonary epithelial cells leads to suppression of LPS or virus induced interferon responses. The levels or LUCAT1 are also lower in systemic lupus erythematosus (SLE) patients. Yet, the role of LUCAT1 in vivo and its contribution to autoimmune disorders is currently unknown. This study aims to elucidate the in vivo functions of LUCAT1 through characterization of a LUCAT1-deficient mouse and to investigate the contribution of LUCAT1 to SLE. The ability of LUCAT1 to restrain immune responses may have a protective effect on the pathogenesis of SLE. Moreover, we will analyze if the anti-inflammatory metabolite itaconate is able to induce LUCAT1 expression through activation of the transcription factor Nrf2. Since LUCAT1 is a potent repressor of immune responses in myeloid cells, it may be an attractive target for newly developed RNA therapeutics for the treatment of autoimmunity and sterile inflammation.

免疫系统已经演变为捍卫人体免受入侵病原体和异常内源细胞的影响，同时应保护健康细胞免受过度免疫反应。因此，对免疫反应的严格调节是基本的。最近的研究表明，除了蛋白质和microRNA外，长的非编码RNA（LNCRNA）在免疫基因的调节中还具有重要作用。但是，大多数LNCRNA及其在炎症性疾病中的作用仍然难以捉摸。几种先天免疫受体激活后，长长的基因间非编码RNA Lucat1（LincRNA-LUCAT1）上调，并对促炎和干扰素刺激的基因的表达产生负调节。 lucat1缺陷的人吞噬细胞在刺激后，尤其是干扰素刺激的基因（ISG）的表达显着增加，而Lucat1在THP1或肺上皮细胞中过表达会导致LPS或病毒诱导的干扰素反应抑制。全身性红斑狼疮（SLE）患者的水平或Lucat1也较低。然而，Lucat1在体内的作用及其对自身免疫性疾病的贡献目前尚不清楚。这项研究旨在通过表征Lucat1缺陷小鼠的表征来阐明Lucat1的体内功能，并研究Lucat1对SLE的贡献。 Lucat1限制免疫反应的能力可能对SLE的发病机理具有保护作用。此外，我们将分析抗炎代谢产物Itaconate是否能够通过激活转录因子NRF2诱导Lucat1表达。由于Lucat1是髓样细胞中免疫反应的有效阻遏物，因此它可能是新开发的RNA疗法的有吸引力的靶标，用于治疗自身免疫性和无菌炎症。