General Pathology Section, Department of Medicine, University of Verona, Verona, Italy.
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands.
Front Immunol. 2019 Jan 31;10:100. doi: 10.3389/fimmu.2019.00100. eCollection 2019.
TLR4 activation initiates a signaling cascade leading to the production of type I IFNs and of the downstream IFN-stimulated genes (ISGs). Recently, a number of IFN-induced long non-coding RNAs (lncRNAs) that feed-back regulate the IFN response have been identified. Dysregulation of this process, collectively known as the "Interferon (IFN) Response," represents a common molecular basis in the development of autoimmune and autoinflammatory disorders. Concurrently, alteration of lncRNA profile has been described in several type I IFN-driven autoimmune diseases. In particular, both TLR activation and the upregulation of ISGs in peripheral blood mononuclear cells have been identified as possible contributors to the pathogenesis of systemic sclerosis (SSc), a connective tissue disease characterized by vascular abnormalities, immune activation, and fibrosis. However, hitherto, a potential link between specific lncRNA and the presence of a type I IFN signature remains unclear in SSc. In this study, we identified, by RNA sequencing, a group of lncRNAs related to the IFN and anti-viral response consistently modulated in a type I IFN-dependent manner in human monocytes in response to TLR4 activation by LPS. Remarkably, these lncRNAs were concurrently upregulated in a total of 46 SSc patients in different stages of their disease as compared to 18 healthy controls enrolled in this study. Among these lncRNAs, Negative Regulator of the IFN Response (NRIR) was found significantly upregulated in SSc monocytes, strongly correlating with the IFN score of SSc patients. Weighted Gene Co-expression Network Analysis showed that NRIR-specific modules, identified in the two datasets, were enriched in "type I IFN" and "viral response" biological processes. Protein coding genes common to the two distinct NRIR modules were selected as putative NRIR target genes. Fifteen -predicted NRIR target genes were experimentally validated in NRIR-silenced monocytes. Remarkably, induction of CXCL10 and CXCL11, two IFN-related chemokines associated with SSc pathogenesis, was reduced in NRIR-knockdown monocytes, while their plasmatic level was increased in SSc patients. Collectively, our data show that NRIR affects the expression of ISGs and that dysregulation of NRIR in SSc monocytes may account, at least in part, for the type I IFN signature present in SSc patients.
TLR4 激活启动信号级联反应，导致 I 型干扰素和下游干扰素刺激基因 (ISGs) 的产生。最近，已经鉴定出许多反馈调节 IFN 反应的 IFN 诱导的长非编码 RNA (lncRNA)。这种过程的失调，统称为“干扰素 (IFN) 反应”，是自身免疫和自身炎症性疾病发展的共同分子基础。同时，在几种 I 型 IFN 驱动的自身免疫性疾病中已经描述了 lncRNA 谱的改变。特别是，TLR 激活和外周血单核细胞中 ISGs 的上调已被确定为系统性硬化症 (SSc) 发病机制的可能因素，SSc 是一种以血管异常、免疫激活和纤维化为特征的结缔组织疾病。然而，迄今为止，SSc 中特定 lncRNA 与 I 型 IFN 特征的存在之间的潜在联系尚不清楚。在这项研究中，我们通过 RNA 测序鉴定了一组与 IFN 和抗病毒反应相关的 lncRNA，这些 lncRNA 在人类单核细胞中以 I 型 IFN 依赖性方式一致调节，以响应 TLR4 激活。值得注意的是，与本研究中纳入的 18 名健康对照者相比，这些 lncRNA 在 SSc 患者不同疾病阶段的总共 46 名 SSc 患者中同时上调。在这些 lncRNA 中，负调控 IFN 反应 (NRIR) 在 SSc 单核细胞中明显上调，与 SSc 患者的 IFN 评分强烈相关。加权基因共表达网络分析显示，在两个数据集识别的 NRIR 特异性模块富含“I 型 IFN”和“病毒反应”生物过程。选择两个不同的 NRIR 模块共有的蛋白质编码基因作为可能的 NRIR 靶基因。在 NRIR 沉默的单核细胞中验证了 15 个预测的 NRIR 靶基因。值得注意的是，在 NRIR 敲低的单核细胞中，与 SSc 发病机制相关的两个 IFN 相关趋化因子 CXCL10 和 CXCL11 的诱导减少，而它们的血浆水平在 SSc 患者中增加。总的来说，我们的数据表明 NRIR 影响 ISG 的表达，SSc 单核细胞中 NRIR 的失调至少部分解释了 SSc 患者存在的 I 型 IFN 特征。
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