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

免疫系统已经进化到保护身体免受入侵的病原体和异常内源性细胞的侵害，而健康细胞应该受到保护，免受过度的免疫反应。因此，严格调节免疫反应是至关重要的。近年来的研究表明，除了蛋白质和microRNA外，长链非编码RNA（lncRNA）在免疫基因调控中也具有重要作用。然而，大多数lncRNA的功能及其在炎症性疾病中的作用仍然难以捉摸。长基因间非编码RNA LUCAT 1（lincRNA-LUCAT 1）在激活几种先天免疫受体后上调，并负调节促炎基因和干扰素刺激基因的表达。LUCAT 1缺陷的人吞噬细胞在刺激后显示免疫调节基因特别是干扰素刺激基因（ISG）的表达显著增加，而LUCAT 1在THP 1或肺上皮细胞中的过表达导致LPS或病毒诱导的干扰素应答的抑制。系统性红斑狼疮（SLE）患者的LUCAT 1水平也较低。然而，LUCAT 1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。本研究的目的是阐明LUCAT 1的体内功能，通过LUCAT 1缺陷小鼠的表征，并调查LUCAT 1的SLE的贡献。LUCAT 1抑制免疫应答的能力可能在SLE的发病机制中具有保护作用。此外，我们将分析抗炎代谢物衣康酸是否能够通过激活转录因子Nrf 2诱导LUCAT 1表达。由于LUCAT 1是骨髓细胞中免疫应答的有效阻遏物，因此它可能是用于治疗自身免疫和无菌炎症的新开发的RNA疗法的有吸引力的靶标。

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.