Viral RNA Induces Type I Interferon-Dependent Cytokine Release and Cell Death in Mesangial Cells via Melanoma-Differentiation-Associated Gene-5 Implications for Viral Infection-Associated Glomerulonephritis
Viral RNA Induces Type I Interferon-Dependent Cytokine Release and Cell Death in Mesangial Cells via Melanoma-Differentiation-Associated Gene-5 Implications for Viral Infection-Associated Glomerulonephritis
复制标题
DOI：
10.2353/ajpath.2009.080585
复制
发表时间：
2009-11-01
影响因子：
6
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
--
作者：
Fluer, Katharina;Allam, Ramanjaneyulu;Anders, Hans-Joachim
病毒RNA可通过胞浆中的固有识别受体黑色素瘤分化相关基因(MDA)-5和视黄醇诱导基因(RIG)-I或胞内Toll样受体(TLRs)在树突状细胞中激活干扰素信号。我们假设病毒RNA也会通过TLR依赖和非TLR依赖的途径激活肾小球系膜细胞产生I型干扰素。为了验证这一假设，我们研究了Toll/IL-1受体域包含适配器诱导干扰素-β(TRIF)缺陷的小鼠，它们缺乏TLR3信号的关键适配器。在原代系膜细胞中，Poly I：C RNA介导的干扰素-β诱导部分依赖于TRIF；然而，当Poly I：C RNA与阳离子脂类复合以增强胞浆摄取时，系膜细胞产生大量的干扰素-α和干扰素-β，而不依赖于Trier系膜细胞表达的RIG-I和MDA-5及其线粒体适配器干扰素-β启动子刺激子-1，小干扰RNA研究表明胞浆Poly I：C RNA信号转导需要MDA5而不是RIG-I。此外，系膜细胞在干扰素-α和干扰素-β刺激下产生IL-6，提示系膜细胞具有自分泌促炎作用。事实上，阻断干扰素-αβ或缺乏IFNA受体可减少病毒RNA诱导的IL-6的产生和系膜细胞的凋亡细胞死亡。此外，病毒RNA/阳离子脂质复合体增加了小鼠肾毒性血清肾炎的局灶性坏死，并与肾脏干扰素相关基因的mRNA表达增加有关。因此，TLR非依赖的病毒RNA识别是系膜细胞中I型干扰素的有效诱导剂，而I型干扰素可能是病毒诱导的肾小球肾炎的重要介导物。(Am J Pathol 20091752014-2022年；DOI：10.2353/ajpath.2009.080585)
Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanoma-differentiation-associated gene (MDA)-5 and retinod-inducible gene (RIG)-I in the cytosol or via Toll-like receptors (TLRs) in intracellular endosomes. We hypothesized that viral RNA would also activate glomerular mesangial cells to produce type I interferon (IFN) via TLR-dependent and TLR-independent pathways. To test this hypothesis, we examined Toll/Interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial cells, poly I:C RNA-mediated IFN-beta induction was partially TRIF dependent; however, when poly I:C RNA was complexed with cationic lipids to enhance cytosolic uptake, mesangial cells produced large amounts of IFN-alpha and IFN-beta independent of TRIER Mesangial cells expressed RIG-I and MDA-5 and their mitochondrial adaptor IFN-beta promoter stimulator-1 as well, and small interfering RNA studies revealed that MDA5 but not RIG-I was required for cytosolic poly I:C RNA signaling. In addition, mesangial cells produced Il-6 on stimulation with IFN-alpha and IFN-beta, suggesting an autocrine proinflammatory effect. indeed, blockade of IFN-alpha beta or lack of the IFNA receptor reduced viral RNA-induced Il-6 production and apoptotic cell death in mesangial cells. Furthermore, viral RNA/cationic lipid complexes increased focal necrosis in murine nephrotoxic serum nephritis in association with increased renal mRNA expression of IFN-related genes. Thus, TLR-independent recognition of viral RNA is a potent inducer of type I interferon in mesangial cells, which can be an important mediator of virally induced glomerulonephritis. (Am J Pathol 2009, 175:2014-2022; DOI: 10.2353/ajpath.2009.080585)