Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible gene (RIG)-1
Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible gene (RIG)-1
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DOI：
10.1093/ndt/gfp339
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发表时间：
2009-11-01
影响因子：
6.1
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
--
作者：
Haegele, Holger;Allam, Ramanjaneyulu;Anders, Hans-Joachim
背景病毒感染触发肾小球肾炎的分子病理机制仍然难以捉摸。在肾小球中，肾小球内皮细胞（GEnC）首先与循环病毒颗粒相互作用，因此，我们假设，病毒RNA，一种已知的诱导剂I型干扰素和细胞因子的树突状细胞，也会引起促炎性抗病毒反应GEnC。用poly I：C RNA刺激培养的鼠GEnC，并评估表型变化。使用特异性拮抗剂或s.i.RNA来确定RNA摄取的机制和假定的RNA受体的功能作用。Poly I：C RNA激活GEnC以产生IL-6、CCL 2、CCL 5、CXCL 10、IFN-α和IFN-β。这与内体酸化或MyD 88无关，但需要与阳离子脂质形成复合物，以通过网格蛋白依赖性内吞作用进入GEnC。RIG-1而非MDA 5特异性s. i. RNA阻止了GEnC活化。I型干扰素的产生并不以自分泌-旁分泌的方式激活GEnC。复合RNA还激活GEnC表达ICAM-1，并增加GEnC单层的白蛋白通透性。复合的dsRNA通过网格蛋白内吞作用进入GEnC，并通过胞质溶胶中的RIG-1激活GEnC以产生炎性细胞因子、趋化因子和I型干扰素。此外，RNA诱导ICAM-1表达并增加GEnC渗透性。所有这些机制可能有助于与RNA病毒感染相关的肾小球肾炎的发作或加重。
Background. The molecular pathomechanisms by which viral infections trigger glomerulonephritis remain elusive. In the glomerulus, glomerular endothelial cells (GEnC) first interact with circulating viral particles; hence, we hypothesized that viral RNA, a known inducer of type I interferons and cytokines in dendritic cells, would also elicit proinflammatory antiviral reponses in GEnC.Methods. Cultured murine GEnC were stimulated with poly I:C RNA and phenotype changes were assessed. Specific antagonists or s.i.RNA were used to determine the mechanisms of RNA uptake and the functional role of putative RNA receptors.Results. Poly I:C RNA activated GEnC to produce IL-6, CCL2, CCL5, CXCL10, IFN-alpha and IFN-beta. This was independent of endosomal acidification or MyD88 but required complex formation with cationic lipids to be taken up into GEnC via clathrin-dependent endocytosis. RIG-1 but not MDA5-specific s.i.RNA prevented GEnC activation. Type I interferon production did not activate GEnC in an autocrine-paracrine manner. Complexed RNA also activated GEnC to express ICAM-1 and increased the albumin permeability of GEnC monolayers.Conclusions. Complexed dsRNA enters GEnC via clathrin endocytosis and activates GEnC via RIG-1 in the cytosol to produce inflammatory cytokines, chemokines and type I interferons. Furthermore, RNA induces ICAM-1 expression and increases GEnC permeability. All of these mechanisms may contribute to the onset or aggravation of glomerulonephritis associated with RNA virus infections.