Lamivudine Inhibits Alu RNA-induced Retinal Pigment Epithelium Degeneration via Anti-inflammatory and Anti-senescence Activities
Lamivudine Inhibits Alu RNA-induced Retinal Pigment Epithelium Degeneration via Anti-inflammatory and Anti-senescence Activities
复制标题
拉米夫定通过抗炎和抗衰老活性抑制 Alu RNA 诱导的视网膜色素上皮变性
DOI：
10.1167/tvst.9.8.1
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Terasaki H.
中科院分区：
文献类型：
--
作者：
Yamada K;Kaneko H*;Shimizu H;Suzumura A;Namba R;Takayama K;Ito S;Sugimoto M;Terasaki H.
目的：长非编码 Alu 元件 RNA 的积累会激活 NLRP3 炎症小体并导致视网膜色素上皮 (RPE) 细胞死亡，这是晚期年龄相关性黄斑变性期间地理萎缩发病机制中的一个关键事件。拉米夫定 (3TC) 是一种核苷类似物逆转录酶抑制剂，已知可抑制 NLRP3 炎症小体。目前，衰老标记物 p16 Ink4a 对长非编码 RNA 的细胞内反应正在积极研究。本研究旨在通过评估 RPE 细胞中促炎细胞因子 IL-18 和 IL-1β 以及 p16 INK4a 表达的变化来评估 3TC 对抗 Alu RNA 诱导的 RPE 炎症和衰老的功效。方法：用体外转录的 Alu RNA 转染培养的人 RPE 细胞和体内小鼠 RPE 细胞，并观察 在 3TC 或 3, 4-(M) CA 作为阴性对照的情况下测量 IL-18、IL-1β 和 p16 Ink4a 表达。结果：与阴性对照相比，用 3TC 处理可显着降低人和小鼠 RPE 细胞中 Alu RNA 诱导的 IL-18 和 IL-1β 表达。此外，在人 RPE 细胞中，Alu RNA 诱导的 p16 INK4a 表达被 3TC 抑制。结论：我们的数据表明，Alu RNA 积累有助于年龄相关性黄斑变性中的 RPE 细胞衰老，并且这种致病过程可以被 3TC 抑制。转化相关性：进一步验证这项研究为年龄相关性黄斑变性治疗提供了潜在靶点。
Purpose: Accumulation of the long noncoding Alu element RNA activates the NLRP3 inflammasome and leads to retinal pigment epithelium (RPE) cell death, a key event in the pathogenesis of geographic atrophy during late-stage age-related macular degeneration. Lamivudine (3TC) is a nucleoside analog reverse transcriptase inhibitor known to inhibit the NLRP3 inflammasome. Currently, the intracellular response of the senescence marker p16 Ink4a to the long noncoding RNA is being actively studied. The present study aimed to assess the efficacy of 3TC against Alu RNA-induced RPE inflammation and senescence by evaluating changes in expression of the proinflammatory cytokines IL-18 and IL-1β and of p16 INK4a in RPE cells.Methods: Cultured human RPE cells and in vivo mouse RPE cells were transfected with an in vitro-transcribed Alu RNA, and changes in IL-18, IL-1β, and p16 Ink4a expression measured in the presences of 3TC or 3, 4-(M) CA as a negative control.Results: Treatment with 3TC markedly reduced Alu RNA-induced expression of IL-18 and IL-1β in human and mouse RPE cells compared with the negative control. Further, Alu RNA-induced p16 INK4a expression was suppressed by 3TC in human RPE cells.Conclusions: Our data suggest that Alu RNA accumulation contributes to RPE cell senescence in age-related macular degeneration and that this pathogenic process can be suppressed by 3TC.Translational Relevance: Further verifying this study leads to potential targets for age-related macular degeneration therapy.