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病原体和异常内源性细胞的侵害，而健康细胞应该受到过度免疫反应的保护。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microRNAs外，长链非编码rna （long non-coding rna, lncRNAs）在免疫基因调控中也发挥着重要作用。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 LUCAT1 （lincRNA-LUCAT1）在激活几种先天免疫受体后上调，负向调节促炎和干扰素刺激基因的表达。缺乏LUCAT1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（ISGs）的表达显著增加，而在THP1或肺上皮细胞中过度表达LUCAT1导致LPS或病毒诱导的干扰素反应受到抑制。系统性红斑狼疮（SLE）患者的LUCAT1水平也较低。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。本研究旨在通过对LUCAT1缺失小鼠的表征来阐明LUCAT1在体内的功能，并探讨LUCAT1在SLE中的作用。LUCAT1抑制免疫应答的能力可能对SLE的发病机制有保护作用。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Nrf2诱导LUCAT1的表达。由于LUCAT1是骨髓细胞免疫反应的有效抑制因子，它可能是新开发的RNA疗法治疗自身免疫和无菌炎症的一个有吸引力的靶点。

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.