Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis
Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis
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DOI：
10.1016/j.jphotobiol.2016.05.018
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发表时间：
2016-08-01
影响因子：
5.4
通讯作者：
Krohne, Tim U.
中科院分区：
文献类型：
--
作者：
Brandstetter, Carolina;Patt, Joshua;Krohne, Tim U.
视网膜色素上皮（RPE）细胞的进行性死亡是年龄相关性黄斑变性（AMD）的标志，AMD是所有发达国家致盲的主要原因。光氧化损伤和NLRP 3炎性体的活化已被认为是该过程的促成因素。我们研究了炎性体激活对氧化损伤诱导的RPE细胞死亡的影响。在原代人RPE细胞和ARPE-19细胞中，脂褐质在与氧化修饰的感光细胞外节孵育后积累。蓝光照射（主波长：448 nm，辐照度：0.8 mW/cm（2），持续时间：3 ~ 6 h）脂褐素负载细胞诱导氧化应激，并通过凋亡导致细胞死亡。通过IL-1 α或补体激活产物C5 a的先前炎性小体引发将细胞死亡机制改变为焦亡，并导致光毒性效应的显著增加。IL-1 α之后。照射后24小时，原代RPE细胞和ARPE-19细胞的存活率分别从653%和56.7%降低至22.6%（p = 0.003）和5.1%（p = 0.0002）。炎性小体介导的IL-1 β释放仅与细胞裂解相关。炎性小体引发的条件培养基的pyroptotic细胞同样增加细胞死亡。通过抑制半胱天冬酶-1或组织蛋白酶B和L抑制炎性小体活化显著减少了致敏细胞中的细胞死亡。总之，由IL-1 α、C5 a或焦亡细胞的条件培养基引发的炎性小体增加了RPE细胞对光氧化损伤介导的细胞死亡的易感性，并将诱导的细胞死亡的机制从凋亡改变为焦亡。这一过程可能导致AMD中的RPE变性，并为干预提供了新的靶点。(C)© 2016 Elsevier B. V.版权所有。
Progressive death of retinal pigment epithelium (RPE) cells is a hallmark of age-related macular degeneration (AMD), the leading cause of blindness in all developed countries. Photooxidative damage and activation of the NLRP3 inflammasome have been suggested as contributing factors to this process. We investigated the effects of inflammasome activation on oxidative damage-induced RPE cell death. In primary human RPE cells and ARPE-19 cells, lipofuscin accumulated following incubation with oxidatively modified photoreceptor outer segments. Oxidative stress was induced by blue light irradiation (dominant wavelength: 448 nm, irradiance: 0.8 mW/cm(2), duration: 3 to 6 h) of lipofuscin-loaded cells and resulted in cell death by apoptosis. Prior inflammasome priming by IL-1 alpha or complement activation product C5a altered the cell death mechanism to pyroptosis and resulted in a significant increase of the phototoxic effect. Following IL-1 alpha. priming, viability 24 h after irradiation was reduced in primary RPE cells and ARPE-19 cells from 653% and 56.7% to 22.6% (p = 0.003) and 5.1% (p = 0.0002), respectively. Inflammasome-mediated IL-1 beta release occurred only in association with pyroptotic cell lysis. Inflammasome priming by conditioned media of pyroptotic cells likewise increased cell death. Suppression of inflammasome activation by inhibition of caspase-1 or cathepsins B and L significantly reduced cell death in primed cells. In summary, inflammasome priming by IL-1 alpha, C5a, or conditioned media of pyroptotic cells increases RPE cell susceptibility to photooxidative damage-mediated cell death and changes the mechanism of induced cell death from apoptosis to pyroptosis. This process may contribute to RPE degeneration in AMD and provide new targets for intervention. (C) 2016 Elsevier B.V. All rights reserved.