Endogenous mitochondrial double-stranded RNA is not an activator of the type I interferon response in human pancreatic beta cells.
Endogenous mitochondrial double-stranded RNA is not an activator of the type I interferon response in human pancreatic beta cells.
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DOI：
10.1186/s13317-021-00148-2
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发表时间：
2021-03-27
期刊：
影响因子：
--
通讯作者：
Eizirik DL
中科院分区：
文献类型：
--
作者：
Coomans de Brachène A;Castela A;Musuaya AE;Marselli L;Marchetti P;Eizirik DL
1 型糖尿病 (T1D) 是一种自身免疫性疾病，其特征是胰腺 β 细胞进行性破坏。干扰素-α (IFNα) 是一种抗病毒细胞因子，在 T1D 早期的胰岛中表达，这可能继发于病毒感染。然而，并非所有携带 I 型干扰素特征的患者都会出现病毒感染信号，这表明这种反应可能是由其他“危险信号”引发的。线粒体双链 RNA（mtdsRNA；一种危险信号）的积累，继发于线粒体降解体成员 PNPT1 和 SUV3 的沉默，已被描述为激活先天免疫反应。为了评估 mtdsRNA 是否代表 T1D 背景下胰腺 β 细胞的“危险信号”，我们沉默了缓慢增殖的人胰岛素分泌 EndoC-βH1 细胞和非增殖的原代人 β 细胞中的 PNPT1 和/或 SUV3，并通过免疫荧光评估了 dsRNA 积累，并通过蛋白质印迹和 RT-qPCR 评估了 I 型 IFN 反应。仅同时沉默 PNPT1/SUV3 会诱导 EndoC-βH1 细胞中 dsRNA 积累，但不会诱导分散的人胰岛，并且不会诱导 I 型 IFN 反应。相比之下，单独沉默这两个基因足以诱导人胰岛制剂中成纤维细胞中 dsRNA 的积累。这些数据表明，降解体敲低后内源性 mtdsRNA 的积累取决于细胞的增殖能力，而不是人胰腺 β 细胞中 I 型 IFN 应答的介质。
Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to viral infections. However, not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other “danger signals”. Accumulation of mitochondrial double-stranded RNA (mtdsRNA; a danger signal), secondary to silencing of members of the mitochondrial degradosome, PNPT1 and SUV3, has been described to activate the innate immune response. To evaluate whether mtdsRNA represents a “danger signal” for pancreatic beta cells in the context of T1D, we silenced PNPT1 and/or SUV3 in slowly proliferating human insulin-secreting EndoC-βH1 cells and in non-proliferating primary human beta cells and evaluated dsRNA accumulation by immunofluorescence and the type I IFN response by western blotting and RT-qPCR. Only the simultaneous silencing of PNPT1/SUV3 induced dsRNA accumulation in EndoC-βH1 cells but not in dispersed human islets, and there was no induction of a type I IFN response. By contrast, silencing of these two genes individually was enough to induce dsRNA accumulation in fibroblasts present in the human islet preparations. These data suggest that accumulation of endogenous mtdsRNA following degradosome knockdown depends on the proliferative capacity of the cells and is not a mediator of the type I IFN response in human pancreatic beta cells.
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