Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.
University Medical Center Utrecht, Department of Rheumatology and Clinical Immunology, Utrecht University, 3584 CX Utrecht, The Netherlands.
Int J Mol Sci. 2021 Apr 22;22(9):4365. doi: 10.3390/ijms22094365.
Systemic sclerosis (SSc) is a chronic autoimmune disease mainly affecting the connective tissue. In SSc patients, monocytes are increased in circulation, infiltrate affected tissues, and show a pro-inflammatory activation status, including the so-called interferon (IFN) signature. We previously demonstrated that the dysregulation of the IFN response in SSc monocytes is sustained by altered epigenetic factors as well as by upregulation of the long non-coding RNA (lncRNA) NRIR. Considering the enormously diverse molecular functions of lncRNAs in immune regulation, the present study investigated the genome-wide profile of lncRNAs in SSc monocytes, with the aim to further unravel their possible role in monocyte dysregulation and disease pathogenesis. Transcriptomic data from two independent cohorts of SSc patients identified 886 lncRNAs with an altered expression in SSc monocytes. Differentially expressed lncRNAs were correlated with neighboring protein coding genes implicated in the regulation of IFN responses and apoptotic signaling in SSc monocytes. In parallel, gene co-expression network analysis identified the lncRNA PSMB8-AS1 as a top-ranking hub gene in co-expression modules implicated in cell activation and response to viral and external stimuli. Functional characterization of PSMB8-AS1 in monocytes demonstrated that this lncRNA is involved in the secretion of IL-6 and TNFα, two pivotal pro-inflammatory cytokines altered in the circulation of SSc patients and associated with fibrosis and disease severity. Collectively, our data showed that lncRNAs are linked to monocyte dysregulation in SSc, and highlight their potential contribution to disease pathogenesis.
系统性硬化症（SSc）是一种主要影响结缔组织的慢性自身免疫性疾病。在 SSc 患者中，循环中的单核细胞增加，浸润受影响的组织，并表现出促炎激活状态，包括所谓的干扰素（IFN）特征。我们之前证明，SSc 单核细胞中 IFN 反应的失调是由改变的表观遗传因素以及长非编码 RNA（lncRNA）NRIR 的上调维持的。考虑到 lncRNA 在免疫调节中的分子功能非常多样化，本研究调查了 SSc 单核细胞中 lncRNA 的全基因组谱，目的是进一步揭示它们在单核细胞失调和疾病发病机制中的可能作用。来自两个独立的 SSc 患者队列的转录组数据鉴定出 886 个在 SSc 单核细胞中表达改变的 lncRNA。差异表达的 lncRNA 与邻近的蛋白编码基因相关，这些基因涉及 SSc 单核细胞中 IFN 反应和凋亡信号的调节。同时，基因共表达网络分析确定 lncRNA PSMB8-AS1 是与细胞激活以及对病毒和外部刺激的反应相关的共表达模块中的顶级枢纽基因。在单核细胞中对 PSMB8-AS1 的功能特征分析表明，该 lncRNA 参与 IL-6 和 TNFα 的分泌，这两种细胞因子在 SSc 患者的循环中发生改变，与纤维化和疾病严重程度相关。总之，我们的数据表明，lncRNA 与 SSc 中的单核细胞失调有关，并强调了它们对疾病发病机制的潜在贡献。
