Guo Tuanmao, Xing Yanli, Chen Zhongning, Zhu Haiyun, Yang Lan, Xiao Yuan, Xu Jiang
Department of Orthopedics, Xianyang Central Hospital, Xianyang, 712000, People's Republic of China.
Department of Pharmacy, Xianyang Central Hospital, No. 78, Renmin East Road, Xianyang, 712000, People's Republic of China.
Inflammation. 2022 Feb;45(1):100-115. doi: 10.1007/s10753-021-01531-x. Epub 2021 Nov 13.
Rheumatoid arthritis (RA) is chronic inflammatory autoimmune disease. The crucial role of long non-coding RNA (lncRNA) in the progression of RA has been highlighted. Hence, this study was designed to explore the specific downstream mechanism of lncRNA nuclear-enriched abundant transcript 1 (NEAT1) in RA. Initially, the expression of NEAT1, p-p65, p300, and IL-18 in clinical tissues and cells was determined. Then, interactions among p65, NEAT1, p300, CBP, and IL-18 were investigated by immunofluorescence staining, dual luciferase reporter gene assay, RT-qPCR assay ChIP assay, and RIP assay followed by the analysis of their effects on RA in vivo and in vitro after expression alteration. The expressions of NEAT1, p-p65, p300, and IL-18 were all upregulated in the synovial tissues from the mice and patients with RA. NEAT1 silencing reduced the infiltration of CD4 T cells and macrophages in synovial tissues, downregulated expression of blood inflammatory factors, relieved RA severity, and lowered incidence of RA in mice. Further, p-p65 could increase the expression of NEAT1 by binding to the NEAT1 promoter region, NEAT1 could co-locate and interact with p300, thus regulating the expression of IL-18 by regulating histone acetylation modification in IL-18 promoter region. NEAT1 aggravated RA via p300/CBP/IL-18 axis, representing a promising therapeutic target in RA.
类风湿性关节炎（RA）是一种慢性炎症性自身免疫性疾病。长链非编码RNA（lncRNA）在RA进展中的关键作用已得到凸显。因此，本研究旨在探讨lncRNA核富集丰富转录本1（NEAT1）在RA中的具体下游机制。首先，测定临床组织和细胞中NEAT1、p-p65、p300和IL-18的表达。然后，通过免疫荧光染色、双荧光素酶报告基因测定、RT-qPCR测定、染色质免疫沉淀（ChIP）测定和RNA免疫沉淀（RIP）测定研究p65、NEAT1、p300、CBP和IL-18之间的相互作用，随后在表达改变后分析它们在体内和体外对RA的影响。RA小鼠和患者滑膜组织中NEAT1、p-p65、p300和IL-18的表达均上调。沉默NEAT1可减少滑膜组织中CD4 T细胞和巨噬细胞的浸润，下调血液炎症因子的表达，减轻RA严重程度，并降低小鼠RA的发病率。此外，p-p65可通过与NEAT1启动子区域结合来增加NEAT1的表达，NEAT1可与p300共定位并相互作用，从而通过调节IL-18启动子区域的组蛋白乙酰化修饰来调节IL-18的表达。NEAT1通过p300/CBP/IL-18轴加重RA，是RA中一个有前景的治疗靶点。
