An activated unfolded protein response promotes retinal degeneration and triggers an inflammatory response in the mouse retina.
An activated unfolded protein response promotes retinal degeneration and triggers an inflammatory response in the mouse retina.
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DOI：
10.1038/cddis.2014.539
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发表时间：
2014-12-18
影响因子：
9
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中科院分区：
文献类型：
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近期关于内质网应激的研究表明，未折叠蛋白反应（UPR）与突变视紫红质导致的遗传性视网膜变性的发病机制有关。然而，UPR激活是否真的会引发视网膜变性这一关键问题仍有待解决。因此，在本研究中，我们构建了一种由持续激活的UPR导致视网膜变性的小鼠模型，以评估与这种疾病状态相关的生理和形态学参数，并揭示UPR促进视网膜变性的潜在机制。我们向C57BL6小鼠眼内注射已知的未折叠蛋白反应（UPR）诱导剂衣霉素（Tn），并通过视网膜电图（ERG）、光谱域光学相干断层扫描（SD - OCT）和组织学分析对小鼠进行检测。治疗30天后，我们检测到光感受器功能显著丧失（超过60%），视网膜结构也出现35%的损伤。对视网膜蛋白提取物的分析表明，包括白细胞介素 - 1β（IL - 1β）、IL - 6、肿瘤坏死因子 - α（TNF - α）、单核细胞趋化蛋白 - 1（MCP - 1）和IBA1在内的炎症标志物显著上调。同样，我们在表达Ter349Glu或T17M视紫红质（RHO）的小鼠中检测到强烈的炎症反应。这些突变的视紫红质会诱导严重的视网膜变性，并且T17M视紫红质在小鼠中表达时会引发UPR激活。RNA和蛋白质分析显示，在表达突变视紫红质的视网膜中，促炎和抗炎标志物如IL - 1β、IL - 6、p65核因子κB（NF - κB）和MCP - 1显著上调，同时F4/80和IBA1小胶质细胞标志物也被激活。然后，我们通过向C57BL6小鼠注射重组IL - 1β来评估Tn诱导的炎症标志物IL - 1β是否能够诱导视网膜变性。与对照视网膜相比，我们观察到ERG a波振幅降低约19%，光感受器细胞损失29%，这表明促炎细胞因子与视网膜病理生理效应之间可能存在潜在联系。我们的研究表明，在已建立的眼部疾病动物模型中，UPR的持续激活可能通过UPR诱导的促炎细胞因子IL - 1β来促进视网膜变性。
Recent studies on the endoplasmic reticulum stress have shown that the unfolded protein response (UPR) is involved in the pathogenesis of inherited retinal degeneration caused by mutant rhodopsin. However, the main question of whether UPR activation actually triggers retinal degeneration remains to be addressed. Thus, in this study, we created a mouse model for retinal degeneration caused by a persistently activated UPR to assess the physiological and morphological parameters associated with this disease state and to highlight a potential mechanism by which the UPR can promote retinal degeneration. We performed an intraocular injection in C57BL6 mice with a known unfolded protein response (UPR) inducer, tunicamycin (Tn) and examined animals by electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT) and histological analyses. We detected a significant loss of photoreceptor function (over 60%) and retinal structure (35%) 30 days post treatment. Analysis of retinal protein extracts demonstrated a significant upregulation of inflammatory markers including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and IBA1. Similarly, we detected a strong inflammatory response in mice expressing either Ter349Glu or T17M rhodopsin (RHO). These mutant rhodopsin species induce severe retinal degeneration and T17M rhodopsin elicits UPR activation when expressed in mice. RNA and protein analysis revealed a significant upregulation of pro- and anti-inflammatory markers such as IL-1β, IL-6, p65 nuclear factor kappa B (NF-kB) and MCP-1, as well as activation of F4/80 and IBA1 microglial markers in both the retinas expressing mutant rhodopsins. We then assessed if the Tn-induced inflammatory marker IL-1β was capable of inducing retinal degeneration by injecting C57BL6 mice with a recombinant IL-1β. We observed ~19% reduction in ERG a-wave amplitudes and a 29% loss of photoreceptor cells compared with control retinas, suggesting a potential link between pro-inflammatory cytokines and retinal pathophysiological effects. Our work demonstrates that in the context of an established animal model for ocular disease, the persistent activation of the UPR could be responsible for promoting retinal degeneration via the UPR-induced pro-inflammatory cytokine IL-1β.
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影响因子：
11.4
作者：
Mendes, Cesar S.;Levet, Clemence;Mollereau, Bertrand
通讯作者：
Mollereau, Bertrand
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG
影响因子：
5.3
作者：
Namekata, Kazuhiko;Harada, Chikako;Harada, Takayuki
通讯作者：
Harada, Takayuki
影响因子：
3.4
作者：
Chen, L;Wu, W;Dunaief, JL
通讯作者：
Dunaief, JL
DOI：
10.1111/j.1651-2227.2010.01836.x
发表时间：
2010-07
期刊：
Acta paediatrica (Oslo, Norway : 1992)
影响因子：
--
作者：
Dammann O
通讯作者：
Dammann O