Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration
Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration
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DOI：
10.1038/cdd.2013.109
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发表时间：
2014-02-01
影响因子：
12.4
通讯作者：
Vavvas, D. G.
中科院分区：
文献类型：
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作者：
Murakami, Y.;Matsumoto, H.;Vavvas, D. G.
没有已知的治疗干燥形式的老年性黄斑变性（AMD）。细胞死亡和炎症是重要的生物学过程，被认为在AMD中起核心作用。在这里，我们发现受体相互作用蛋白（RIP）激酶在由dsRNA （AMD中drusen的一个组成部分）诱导的视网膜变性小鼠模型中介导坏死并增强炎症。与光感受器诱导的细胞凋亡相反，视网膜下注射dsRNA类似物poly（I: C）导致视网膜色素上皮（RPE）坏死，以及巨噬细胞向视网膜外浸润。在Rip3（-/-）小鼠中，坏死和炎症都被阻止，对poly（I: C）诱导的视网膜变性提供了实质性的保护。此外，poly（I: C）注射后，Rip3（-/-）小鼠显示视网膜中促炎细胞因子（如tnf - α和IL-6）水平降低，玻璃体内高迁移率组盒1 （HMGB1）的释放减弱，这是一种主要的损伤相关分子模式（DAMP）。在体外，poly（I: C）诱导的坏死在rip3缺失的RPE细胞中被抑制，从而抑制HMGB1的释放，并抑制坏死上清诱导的tnf - α和IL-6的诱导。另一方面，Rip3缺乏并不直接调节RPE细胞或巨噬细胞poly（I: C）刺激后tnf - α和IL-6的产生。因此，程序性坏死在dsrna诱导的视网膜变性中至关重要，并可能通过调节细胞内DAMPs的释放来促进炎症，这为AMD等疾病提供了新的治疗靶点。
There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I : C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3(-/-) mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I : C)-induced retinal degeneration. Moreover, after poly(I : C) injection, Rip3(-/-) mice displayed decreased levels of pro-inflammatory cytokines (such as TNF-alpha and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I : C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF-alpha and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-alpha and IL-6 production after poly(I : C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.