Photoreceptor cell (PHR) death is a hallmark of most retinal neurodegenerative diseases, in which inflammation plays a critical role. Activation of retinoid X receptors (RXR) modulates and integrates multiple cell functions, and has beneficial effects in animal models of chronic inflammatory diseases. Nonetheless, the mechanisms involved and their role in retina neuroprotection are poorly understood. In this work we assessed whether RXR activation prevents inflammation and/or PHR death in retinitis pigmentosa, an inherited retina neurodegeneration, using as an ex vivo model, retinas from the rd1 mice, a murine model of this disease. We demonstrated that rd1 retinas had lower levels of RXR alpha isoform than their wt counterparts at early developmental times, whereas its distribution pattern remained similar. In mixed neuro-glial cultures obtained from either rd1 or wt retinas, both PHR and Müller glial cells (MGC) expressed RXRalpha, and RXR activation by its synthetic pan-agonist PA024 selectively increased mRNA levels of RXRgamma isoform. PA024 decreased PHR death in rd1 mixed cultures; it reduced the amount of non-viable neurons, delayed the onset of PHR apoptosis, and decreased Bax mRNA levels. PA024 also reduced MGC reactivity in vitro before and at the onset of degeneration, decreasing GFAP expression, increasing glutamine synthetase mRNA levels, and promoting the transcription of the anti-inflammatory cytokine, Il-10. These results suggest that RXR activation rescues rd1 PHR and decreases MGC reactivity, promoting an anti-inflammatory environment in the rd1 retina, thus supporting the potential of RXR agonists as pharmacological tools for treating retina degenerative diseases.

光感受器细胞 (PHR) 死亡是大多数视网膜神经退行性疾病的标志，其中炎症起着关键作用。类视黄醇 X 受体 (RXR) 的激活可调节和整合多种细胞功能，在慢性炎症疾病的动物模型中具有有益作用。尽管如此，所涉及的机制及其在视网膜神经保护中的作用仍知之甚少。在这项工作中，我们评估了 RXR 激活是否可以预防色素性视网膜炎（一种遗传性视网膜神经变性）中的炎症和/或 PHR 死亡，使用rd1小鼠的视网膜作为离体模型，该小鼠模型是该疾病的一种小鼠模型。我们证明了rd1视网膜的 RXR α 异构体水平低于它们的wt早期发展时期的对应物，而其分布模式保持相似。在从rd1或wt视网膜获得的混合神经胶质细胞培养物中，PHR 和 Müller 神经胶质细胞 (MGC) 都表达了 RXRalpha，并且通过其合成泛激动剂 PA024 激活 RXR 选择性地增加了 RXRgamma 异构体的 mRNA 水平。PA024 降低了rd1 中的PHR 死亡混合文化；它减少了无活性神经元的数量，延迟了 PHR 细胞凋亡的发生，并降低了 Bax mRNA 水平。PA024 还在变性之前和开始时降低体外 MGC 反应性，降低 GFAP 表达，增加谷氨酰胺合成酶 mRNA 水平，并促进抗炎细胞因子 Il-10 的转录。这些结果表明 RXR 激活可挽救rd1 PHR 并降低 MGC 反应性，促进rd1视网膜中的抗炎环境，从而支持 RXR 激动剂作为治疗视网膜退行性疾病的药理学工具的潜力。