Fontaine Valérie, Boumedine Thinhinane, Monteiro Elodie, Fournié Mylène, Gersende Gendre, Sahel José-Alain, Picaud Serge, Veillet Stanislas, Lafont René, Latil Mathilde, Dilda Pierre J, Camelo Serge
Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France.
Fondation Ophtalmologique Rothschild, 29 rue Manin, 75019 Paris, France.
Int J Mol Sci. 2024 Mar 6;25(5):3037. doi: 10.3390/ijms25053037.
-retinylidene--retinylethanolamine (A2E) has been associated with age-related macular degeneration (AMD) physiopathology by inducing cell death, angiogenesis and inflammation in retinal pigmented epithelial (RPE) cells. It was previously thought that the A2E effects were solely mediated via the retinoic acid receptor (RAR)-α activation. However, this conclusion was based on experiments using the RAR "specific" antagonist RO-41-5253, which was found to also be a ligand and partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. Moreover, we previously reported that inhibiting PPAR and retinoid X receptor (RXR) transactivation with norbixin also modulated inflammation and angiogenesis in RPE cells challenged in the presence of A2E. Here, using several RAR inhibitors, we deciphered the respective roles of RAR, PPAR and RXR transactivations in an in vitro model of AMD. We showed that BMS 195614 (a selective RAR-α antagonist) displayed photoprotective properties against toxic blue light exposure in the presence of A2E. BMS 195614 also significantly reduced the AP-1 transactivation and mRNA expression of the inflammatory interleukin (IL)-6 and vascular endothelial growth factor (VEGF) induced by A2E in RPE cells in vitro, suggesting a major role of RAR in these processes. Surprisingly, however, we showed that (1) Norbixin increased the RAR transactivation and (2) AGN 193109 (a high affinity pan-RAR antagonist) and BMS 493 (a pan-RAR inverse agonist), which are photoprotective against toxic blue light exposure in the presence of A2E, also inhibited PPARs transactivation and RXR transactivation, respectively. Therefore, in our in vitro model of AMD, several commercialized RAR inhibitors appear to be non-specific, and we propose that the phototoxicity and expression of IL-6 and VEGF induced by A2E in RPE cells operates through the activation of PPAR or RXR rather than by RAR transactivation.
视黄叉基 - 视黄基乙醇胺（A2E）通过诱导视网膜色素上皮（RPE）细胞死亡、血管生成和炎症，与年龄相关性黄斑变性（AMD）的病理生理过程相关。以前认为A2E的作用仅通过视黄酸受体（RAR）-α激活介导。然而，这一结论是基于使用RAR“特异性”拮抗剂RO - 41 - 5253的实验得出的，而该拮抗剂后来被发现也是过氧化物酶体增殖物激活受体（PPAR）-γ的配体和部分激动剂。此外，我们之前报道过，用去甲比妥抑制PPAR和视黄酸X受体（RXR）反式激活也能调节在A2E存在下受到挑战的RPE细胞中的炎症和血管生成。在此，我们使用几种RAR抑制剂，在AMD的体外模型中解析了RAR、PPAR和RXR反式激活各自的作用。我们发现，在A2E存在的情况下，BMS 195614（一种选择性RAR-α拮抗剂）对有毒蓝光暴露具有光保护特性。BMS 195614还显著降低了A2E在体外RPE细胞中诱导的AP - 1反式激活以及炎性白细胞介素（IL）-6和血管内皮生长因子（VEGF）的mRNA表达，表明RAR在这些过程中起主要作用。然而，令人惊讶的是，我们发现：（1）去甲比妥增加了RAR反式激活；（2）AGN 193109（一种高亲和力泛RAR拮抗剂）和BMS 493（一种泛RAR反向激动剂）在A2E存在时对有毒蓝光暴露具有光保护作用，但它们分别也抑制了PPAR反式激活和RXR反式激活。因此，在我们的AMD体外模型中，几种商业化的RAR抑制剂似乎是非特异性的，并且我们提出，A2E在RPE细胞中诱导的光毒性以及IL - 6和VEGF的表达是通过PPAR或RXR的激活而非RAR反式激活起作用的。
