Depletion of the Receptor-Interacting Protein Kinase 3 (RIP3) Decreases Photoreceptor Cell Death During the Early Stages of Ocular Murine Cytomegalovirus Infection.
Depletion of the Receptor-Interacting Protein Kinase 3 (RIP3) Decreases Photoreceptor Cell Death During the Early Stages of Ocular Murine Cytomegalovirus Infection.
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DOI：
10.1167/iovs.18-24086
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发表时间：
2018-05-01
影响因子：
4.4
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Xu J;Mo J;Liu X;Marshall B;Atherton SS;Dong Z;Smith S;Zhang M
本研究的目的是通过比较RIP 3缺失小鼠（RIP 3-/-）和RIP 3 +/+对照小鼠的先天免疫应答和细胞死亡，确定受体相互作用蛋白激酶3（RIP 3）是否在鼠巨细胞病毒（MCMV）视网膜感染期间的先天免疫应答和旁观者视网膜神经元死亡中发挥重要作用。对Rip 3 −/−和Rip 3 +/+小鼠进行免疫抑制（IS），并通过睫状体上途径接种MCMV。在感染后第4、7和10天（p.i.）并分析先天免疫和细胞死亡的标志物。与Rip 3 +/+小鼠相比，在感染后第4天和第7天，在Rip 3 −/−小鼠的注射眼中回收了显著更多的MCMV，并观察到更多的MCMV感染的RPE细胞。相比之下，在Rip 3 −/−眼中观察到的TUNEL染色光感受器比Rip 3 +/+眼中少。电子显微镜显示，Rip 3 +/+小鼠中的凋亡感光细胞明显多于Rip 3 −/−小鼠。免疫组化显示，大多数TUNEL染色的光感受器通过线粒体黄素蛋白凋亡诱导因子（AIF）介导的，caspase 3非依赖性凋亡而死亡。感染眼中的大多数RIP 3表达细胞是RPE细胞、小胶质细胞/巨噬细胞和神经胶质细胞，而视网膜神经元含有低得多的RIP 3。蛋白质印迹显示，与Rip 3 −/−眼相比，Rip 3 +/+眼中活化的核因子-κB和半胱天冬酶1的水平显著更高。我们的研究结果表明，RIP 3通过激活炎性小体和核因子-κB来增强针对眼部MCMV感染的天然免疫应答，这也通过包括凋亡和坏死性凋亡在内的多种途径导致炎症和旁观者细胞死亡。
The purpose of this study was to determine if the receptor-interacting protein kinase 3 (RIP3) plays a significant role in innate immune responses and death of bystander retinal neurons during murine cytomegalovirus (MCMV) retinal infection, by comparing the innate immune response and cell death in RIP3-depleted mice (Rip3−/−) and Rip3+/+ control mice. Rip3−/− and Rip3+/+ mice were immunosuppressed (IS) and inoculated with MCMV via the supraciliary route. Virus-injected and mock-injected control eyes were removed at days 4, 7, and 10 post infection (p.i.) and markers of innate immunity and cell death were analyzed. Compared to Rip3+/+ mice, significantly more MCMV was recovered and more MCMV-infected RPE cells were observed in injected eyes of Rip3−/− mice at days 4 and 7 p.i. In contrast, fewer TUNEL-stained photoreceptors were observed in Rip3−/− eyes than in Rip3+/+ eyes at these times. Electron microscopy showed that significantly more apoptotic photoreceptor cells were present in Rip3+/+ mice than in Rip3−/− mice. Immunohistochemistry showed that the majority of TUNEL-stained photoreceptors died via mitochondrial flavoprotein apoptosis-inducing factor (AIF)-mediated, caspase 3–independent apoptosis. The majority of RIP3-expressing cells in infected eyes were RPE cells, microglia/macrophages, and glia, whereas retinal neurons contained much lower amounts of RIP3. Western blots showed significantly higher levels of activated nuclear factor–κB and caspase 1 were present in Rip3+/+ eyes compared to Rip3−/− eyes. Our results suggest that RIP3 enhances innate immune responses against ocular MCMV infection via activation of the inflammasome and nuclear factor–κB, which also leads to inflammation and death of bystander cells by multiple pathways including apoptosis and necroptosis.
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