Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, 200080, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China.
Tongji Eye Institute, Department of Regenerative Medicine, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China.
Free Radic Biol Med. 2022 Mar;181:14-28. doi: 10.1016/j.freeradbiomed.2022.01.018. Epub 2022 Jan 25.
In the pathogenesis of retinal degenerative diseases, oxidative stress is a key driver leading to photoreceptor death and eventually vision loss. Currently, there are no effective therapies available to rescue photoreceptors in these diseases. High-mobility group box 2 (HMGB2), a pro-inflammatory factor and damage-associated molecular patterns (DAMPs), has been proven to mediate various inflammatory diseases, but its role in retinal degenerative diseases, especially in retinal inflammation and photoreceptor degeneration, still remains unknown. In this study, we assessed the localization and function of HMGB2 under oxidative stress and explored the underlying mechanisms in a mouse model of light-induced retinal damage (LIRD). The results showed that increased oxidative stress, the photoreceptors death, as well as the pyroptosis-related proteins were evidenced in mice retina after light exposure. HMGB2 protein was predominantly expressed in the outer nuclear layer (ONL), which was translocated to the cytoplasm and released after injury. The mechanistic effect of HMGB2 was studied in the 661w cell line treated with HO, showing that exogenous recombinant HMGB2 protein reduced the expressions of the antioxidant protein nuclear erythroid factor 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1), and induced NF-κB/NLRP3 signaling pathway. HMGB2 knockdown increased cell viability, up-regulated the expressions of Nrf2 and HO-1, down-regulated the expressions of pyroptosis-related proteins in HO-treated 661w cells; and also prevented photoreceptors loss and maintained ONL in mice model of LIRD. The present study proposed HMGB2 as a potential therapeutic target for treatment of retinal degenerative diseases.
在视网膜退行性疾病的发病机制中，氧化应激是导致光感受器死亡并最终导致视力丧失的关键因素。目前，尚无有效的治疗方法可用于挽救这些疾病中的光感受器。高迁移率族蛋白 2（HMGB2）是一种促炎因子和损伤相关分子模式（DAMPs），已被证明可介导各种炎症性疾病，但它在视网膜退行性疾病中的作用，特别是在视网膜炎症和光感受器变性中的作用尚不清楚。在这项研究中，我们评估了氧化应激下 HMGB2 的定位和功能，并在光诱导的视网膜损伤（LIRD）小鼠模型中探索了潜在的机制。结果表明，光照后小鼠视网膜中氧化应激增加、光感受器死亡以及与细胞焦亡相关的蛋白增加。HMGB2 蛋白主要在外核层（ONL）表达，损伤后向细胞质移位并释放。在 HO 处理的 661w 细胞系中研究了 HMGB2 的机制作用，结果表明，外源性重组 HMGB2 蛋白降低了抗氧化蛋白核红细胞 2 相关因子 2（Nrf2）及其下游靶血红素加氧酶-1（HO-1）的表达，并诱导了 NF-κB/NLRP3 信号通路。HMGB2 敲低增加了细胞活力，上调了 HO 处理的 661w 细胞中 Nrf2 和 HO-1 的表达，下调了与细胞焦亡相关蛋白的表达；并防止了 LIRD 小鼠模型中光感受器的损失和维持了 ONL。本研究提出 HMGB2 可能是治疗视网膜退行性疾病的潜在治疗靶点。
