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首页> 外文期刊>EBioMedicine >Dual function of miR-1248 links interferon induction and calcium signaling defects in Sj?gren's syndrome
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Dual function of miR-1248 links interferon induction and calcium signaling defects in Sj?gren's syndrome

机译：miR-1248的双重功能链接了干燥综合征的干扰素诱导和钙信号传导缺陷

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Background Sj?gren's syndrome (SS) is one of the most common autoimmune disorders leading to exocrine gland dysfunction. Both immune-dependent processes – like Type I Interferon (IFN) signaling and immune-independent processes – such as calcium signaling in epithelial cells – contribute to disease pathophysiology. However, a mechanistic link between these processes has not been demonstrated. Methods Primary human salivary gland cells were used to evaluate the differential expression of miRNAs with smRNA-seq in primary epithelial cells culture and digital PCR was conducted in SS human salivary glands (SG) biopsies to verify the results. With siRNA screening and pull-down assays to establish the role of miRNA in IFN activation. Findings Activation of IFN-β by miR-1248 is through the direct association with both RIG-I and AGO2. Further functional studies establish a unique dual functional role of miR-1248 in phSG cells: i) activation of the RIG-I pathway by acting as ligand of this sensor leading to IFN production and ii) regulation of the expression of mRNAs through the canonical microRNA function. Importantly, ITPR3, a key component of calcium signaling in epithelial cells, that has previously shown to be downregulated in SS SG, was directly targeted and downregulated by miR-1248, inducing the same functional calcium signaling changes as observed in SS SGs. Interpretation Identification of the first endogenous mammalian microRNA that binds to RIG-I inducing IFN production but also demonstrate a novel pathophysiological underlying mechanism in which miR-1248 overexpression links two major pathways associated with SS, namely activation of IFN production with modulation of calcium signaling. Together, these findings suggest a unifying hypothesis for the immune-independent and -dependent processes contributing to the pathogenesis of SS. Fund This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Dental and Craniofacial Research (NIDCR).
机译：背景干燥综合征（SS）是导致外分泌腺功能障碍的最常见的自身免疫性疾病之一。免疫依赖性过程（例如I型干扰素（IFN）信号转导）和免疫依赖性过程（例如上皮细胞中的钙信号转导）都有助于疾病的病理生理。但是，这些过程之间的机械联系尚未得到证实。方法采用原代人唾液腺细胞评估带有smRNA-seq的miRNA在原代上皮细胞培养物中的差异表达，并在SS人唾液腺（SG）活检组织中进行数字PCR以验证结果。通过siRNA筛选和下拉测定法来确定miRNA在IFN激活中的作用。发现miR-1248对IFN-β的激活是通过与RIG-1和AGO2的直接结合而实现的。进一步的功能研究确立了miR-1248在phSG细胞中的独特双重功能作用：i）通过充当导致IFN产生的该传感器的配体激活RIG-I途径，以及ii）通过规范的microRNA调节mRNA的表达功能。重要的是，miR-1248直接靶向并下调了ITPR3，它是上皮细胞中钙信号传导的关键成分，先前已被证实在SS SG中被下调，从而诱导了与SS SG中观察到的功能性钙信号变化相同的功能。解释鉴定第一个与RIG-I诱导IFN结合的内源性哺乳动物microRNA，但也证明了一种新型的病理生理基础机制，其中miR-1248过表达将与SS相关的两个主要途径联系在一起，即通过调节钙信号传导来激活IFN产生。总之，这些发现提出了促成SS发病机制的免疫独立和依赖过程的统一假说。基金这项研究得到了美国国立卫生研究院（NIH），美国国立牙科和颅面研究所（NIDCR）的内部研究计划的支持。

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