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Repeat exposure to polyinosinic:polycytidylic acid induces TLR3 expression via JAK-STAT signaling and synergistically potentiates NFκB-RelA signaling in ARPE-19 cells.
Cellular Signalling ( IF 4.8 ) Pub Date : 2019-12-04 , DOI: 10.1016/j.cellsig.2019.109494
R Scott Duncan 1 , Landon Rohowetz 1 , Alex Vogt 1 , Peter Koulen 2
Affiliation  

Dry age-related macular degeneration (AMD), accounting for approximately 90% of AMD cases, is characterized by photoreceptor death, retinal pigment epithelium (RPE) dysfunction and, ultimately, geographic atrophy - the localized death of RPE leading to loss of the center of the visual field. The pathological etiology of AMD is multifactorial, but innate immune signaling and inflammation are involved in early stages of the disease. Although numerous single-nucleotide polymorphisms in innate immune genes are associated with dry AMD, no single gene appears to cause dry AMD. Here, we hypothesized that activation of TLR3 potentiates expression of TLR3 itself and the NFκB-p65 (RelA) subunit as part of pro-inflammatory RPE signaling. Furthermore, we hypothesized that TLR3 activation can 'prime' cells to future RelA stimulation, leading to enhanced, persistent RelA expression and signaling following a second TLR3 activation. We used the human RPE-derived cell line ARPE-19 as a model system for RPE signaling and measured NFκB expression and activity in response to TLR3 stimulation with its ligand, polyinosinic:polycytidylic acid (pI:C). Activation of TLR3 with pI:C led to increased TLR3 and RelA expression that was sustained for at least 24 h. Cells exposed for a second time to pI:C after an initial pI:C exposure displayed elevated RelA expression and RelA nuclear translocation above the level generated by individual primary or secondary exposures alone. Such an elevated response could also not be generated by a single application of higher concentrations of the agonist pI:C. Additionally, we determined the mechanism for TLR3 mediated TLR3 and RelA expression by using inhibitors of canonical TLR3-TBK1-IKKε and JAK-STAT signaling pathways. These data suggest that initial exposure of ARPE-19 cells to pI:C upregulates TLR3 and RelA signaling, leading to potentiated and persistent RelA signaling potentially generated by a positive feedback loop that may cause exacerbated inflammation in AMD. Furthermore, inhibition of JAK-STAT signaling may be a possible therapeutic treatment to prevent induction of TLR3 expression subsequent to pI:C exposure. Our results identify possible therapeutic targets to reduce the TLR3 positive feedback loop and subsequent overproduction of pro-inflammatory cytokines in RPE cells.

中文翻译:

重复暴露于多肌苷酸:聚胞苷酸可通过JAK-STAT信号传导诱导TLR3表达,并协同增强ARPE-19细胞中的NFκB-RelA信号传导。

与干龄相关的黄斑变性(AMD)约占AMD病例的90%,其特征是光感受器死亡,视网膜色素上皮(RPE)功能障碍以及最终的地理萎缩-RPE的局部死亡导致中心丧失视野。AMD的病理病因是多因素的,但先天免疫信号和炎症与疾病的早期阶段有关。尽管先天免疫基因中的许多单核苷酸多态性与干性AMD相关,但似乎没有单个基因引起干性AMD。在这里,我们假设激活TLR3会增强TLR3本身和NFκB-p65(RelA)亚基的表达,这是促炎性RPE信号转导的一部分。此外,我们假设TLR3激活可以“引发”细胞以应对未来的RelA刺激,在第二次TLR3激活后导致增强的,持久的RelA表达和信号转导。我们使用人类RPE衍生的细胞系ARPE-19作为RPE信号传导的模型系统,并通过配体多肌苷酸:多胞苷酸(pI:C)响应TLR3刺激,测量了NFκB的表达和活性。用pI:C激活TLR3导致TLR3和RelA表达增加,持续至少24 h。初始pI:C暴露后第二次暴露于pI:C的细胞显示,RelA表达和RelA核易位高于单独的一次或二次暴露所产生的水平。仅通过单次使用较高浓度的激动剂pI:C也不会产生这种升高的反应。此外,我们通过使用规范的TLR3-TBK1-IKKε和JAK-STAT信号通路的抑制剂,确定了TLR3介导的TLR3和RelA表达的机制。这些数据表明,ARPE-19细胞最初暴露于pI:C会上调TLR3和RelA信号转导,导致可能由正反馈环产生的增强的和持久的RelA信号转导,可能导致AMD炎症加重。此外,抑制JAK-STAT信号可能是预防在pI:C暴露后诱导TLR3表达的一种可能的治疗方法。我们的结果确定了可能的治疗靶点,以减少TPE3阳性反馈环和随后在RPE细胞中促炎性细胞因子的过量生产。C上调TLR3和RelA信号转导,导致可能由正反馈回路产生的增强的和持久的RelA信号转导可能会导致AMD炎症加重。此外,抑制JAK-STAT信号可能是预防在pI:C暴露后诱导TLR3表达的一种可能的治疗方法。我们的结果确定了可能的治疗靶点,以减少TPE3阳性反馈环和随后在RPE细胞中促炎性细胞因子的过量生产。C上调TLR3和RelA信号转导,导致可能由正反馈回路产生的增强的和持久的RelA信号转导可能会导致AMD炎症加重。此外,抑制JAK-STAT信号可能是预防在pI:C暴露后诱导TLR3表达的一种可能的治疗方法。我们的结果确定了可能的治疗靶点,以减少TPE3阳性反馈环和随后在RPE细胞中促炎性细胞因子的过量生产。
更新日期:2019-12-04
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