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

免疫系统的进化是为了保护身体免受病原体和异常内源性细胞的侵袭，而健康的细胞应该受到保护，不受过度免疫反应的影响。因此，对免疫反应的严格调控是根本。最近的研究表明，除了蛋白质和microRNAs，长的非编码RNAs(LncRNAs)在免疫基因的调控中也具有重要的作用。然而，大多数lncRNAs的功能及其在炎症性疾病中的作用仍然不清楚。LUCAT1(lincRNA-LUCAT1)是一种长基因间隔型非编码RNA，在多种天然免疫受体激活后表达上调，负向调节促炎基因和干扰素刺激基因的表达。LUCAT1缺陷的人吞噬细胞在刺激后免疫调节基因尤其是干扰素刺激基因(ISGs)的表达显着增加，而在THP1或肺上皮细胞中过表达LUCAT1可抑制内毒素或病毒诱导的干扰素应答。系统性红斑狼疮(SLE)患者的LUCAT1水平也较低。然而，LUCAT1在体内的作用及其在自身免疫性疾病中的作用目前尚不清楚。本研究旨在通过对LUCAT1缺陷小鼠的鉴定，阐明LUCAT1在体内的功能，并探讨LUCAT1在系统性红斑狼疮中的作用。LUCAT1抑制免疫反应的能力可能在SLE的发病机制中起到保护作用。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来诱导LUCAT1的表达。由于LUCAT1是一种有效的髓系细胞免疫反应抑制因子，它可能是治疗自身免疫和无菌炎症的新开发的RNA疗法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.